JPH021826B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel aminonaphthacene derivatives and production methods. For more details, see the general formula [In the formula, R ₁ means a hydrogen atom or -COR ₇ . R ₂ and R ₃ together mean an ethylenedioxy group or an oxo group. R ₄ and R ₅ both represent a hydrogen atom, or one represents a hydrogen atom and the other represents -COR ₇ . R ₆ means a hydrogen atom, a hydroxy group or -OCOR ₇ .
R ₇ means a lower alkyl group or a lower halogenoalkyl group. ] This relates to a 9-amino-7,8,9,10-tetrahydronaphthacene derivative represented by the following. The compounds of the present invention have antibacterial and anticancer effects and are useful as pharmaceuticals. The 9-amino-7,8,9,10-tetrahydronaphthacene derivative represented by the general formula [ ] related to the compound of the present invention can be produced by the following method. General formula [] [In the formula, R ₇ has the same meaning as above. ] By reacting the compound represented by phthalic anhydride and Lewis acid in the presence of general formula [] [In the formula, R ₇ has the same meaning as above. ] A compound represented by the following can be obtained. Lewis acids include aluminum chloride, aluminum bromide,
Examples include ferric chloride and tin chloride, but aluminum chloride is preferred because of its ease of availability and handling. Although the reaction can be carried out under the conditions used in ordinary Friedel Crafts reactions, it is preferable to carry out the reaction in the absence of a solvent, by adding a salt such as sodium chloride, and by melt reaction. If necessary, by subjecting the compound represented by the general formula [] to a normal acetalization reaction, the compound represented by the general formula [] [In the formula, R ₇ has the same meaning as above. R ₈ and R ₉ represent an ethylene group. ] A compound represented by the following can be obtained. General formula [] or general formula [] as required
By reacting the compound represented by the formula with a halogenating agent in an appropriate solvent, the compound represented by the general formula [] [In the formula, R ₂ , R ₃ and R ₇ have the same meanings as above. ] A compound represented by the following can be obtained. Suitable examples of the halogenating agent include bromine, chlorine, N-bromosuccinimide, and N-chlorosuccinimide. There are no particular restrictions on the solvent as long as it does not interfere with the progress of the reaction, but examples include carbon tetrachloride, halogenated alkyl solvents such as chloroform, dichloroethane, and tetrachloroethane, ether solvents such as tetrahydrofuran and dioxane, hexane, cyclohexane, and heptane. Aliphatic solvents such as acetone, ketone solvents such as methyl ethyl ketone, benzene, water, acetic acid, etc. can be used alone or in any mixture. Although the reaction proceeds at room temperature, it can also be carried out near the boiling point of the solvent by heating to accelerate the reaction. Further, in order to accelerate the reaction, if necessary, a radical initiator such as N,N'-azobisisobutyronitrile or benzoyl peroxide may be added, or visible light may be irradiated. If necessary, a compound represented by the general formula [] is subjected to a hydrolysis reaction in a water-containing solvent in the presence of a mineral acid such as hydrochloric acid or sulfuric acid, or an organic sulfonic acid such as p-toluenesulfonic acid, to obtain the formula [] A compound represented by can be obtained. Water alone may be used as the solvent, but a mixture of water and an organic solvent may also be used. Organic solvents at this time include alcohol solvents such as methanol, ethanol, and isopropanol, ether solvents such as tetrahydrofuran and dioxane, ketone solvents such as acetone and methyl ethyl ketone, chloroform,
Halogenated alkyl solvents such as dichloroethane,
Mention may be made of solvents such as acetic acid and any mixtures thereof. The reaction proceeds even at room temperature, but in order to accelerate the reaction it can be heated to around the boiling point of the solvent. If necessary, the compound represented by the formula [] can be represented by the general formula [] R ₇ -COOH [] [wherein R ₇ has the same meaning as above]. ] or its reactive derivative and condensed with the general formula [] [In the formula, R ₇ has the same meaning as above. R ₁ is a hydrogen atom or

It means [formula]. ] A compound represented by the following can be obtained. As a condensation method, when a compound represented by the general formula [] is used, a method of reacting in the presence of a dehydrating agent such as dicyclohexylamine can be mentioned, and a reactive derivative of the compound represented by the general formula [] is used. In some cases, a conventional acylation reaction in the presence of a base can be mentioned. By changing the number of moles used in the reaction of the compound or reactive derivative represented by the general formula [] in the above reaction, R ₁ can be a hydrogen atom or

It is possible to obtain any of the compounds that are the group [Formula]. In the general formula [], R ₁ is H
To obtain a compound, the number of moles of the compound represented by the general formula [] or its reactive derivative to be used is 1 to 3 times that of the compound represented by the general formula []. In the formula [], R ₁ is

[Formula] To obtain the compound represented by the group, the number of moles of the compound represented by the general formula [] or its reactive derivative to be used is at least four times that of the compound represented by the general formula []. Can be done. Examples of reactive derivatives include acid halides and acid anhydrides of the compound represented by the general formula []. Suitable examples of the base include sodium carbonate, sodium hydrogencarbonate, triethylamine, pyridine, 4-dimethylaminopyridine, lutidine, and collidine. Examples of solvents include halogenated alkyl solvents such as dichloromethane, chloroform, and dichloroethane, ether solvents such as tetrahydrofuran and dioxane, ketone solvents such as acetone and methyl ethyl ketone, and solvents such as dimethylformamide and dimethyl sulfoxide. However, an oily base may also be used as a solvent. Although the reaction proceeds at room temperature, it can also be heated to around the boiling point of the solvent to accelerate the reaction. If necessary, by subjecting the compound represented by the general formula [] to a normal acetalization reaction, the compound represented by the general formula [] [In the formula, R ₁ , R ₇ , R ₈ and R ₉ have the same meanings as above. ] A compound represented by the following can be obtained. The compound represented by the general formula [], which is a raw material for the synthesis of the compound of the present invention, is a new compound and can be synthesized by the method of reaction formula [A]. Reaction formula [A] [In the formula, R ₇ has the same meaning as above. ] That is, compound (1) is reacted with ammonium carbonate and potassium cyanide to form compound (2), and compound (2) is hydrolyzed in the presence of barium hydroxide to form compound (3).
Compound (3) is expressed by general formula (7) [In the formula, R ₇ has the same meaning as above. ] Or general formula (8) [In the formula, R ₇ has the same meaning as above. ] A conventional acylation reaction is performed with the compound represented by the formula to form compound (4), and then compound (4) is reacted in methanol in the presence of an acid catalyst such as sulfuric acid to form compound (5).
Compound (5) is reacted with methylsulfinyl carbanion prepared from dimethyl sulfoxide and NaH to form compound (6), and when compound (6) is desulfurized with aluminum amalgam or zinc, it is expressed by the general formula []. can be obtained. The compound represented by the general formula [], which is a compound of the present invention, has an asymmetric carbon, but the present invention includes all stereoisomers, and these isomers can be used singly or as a mixture. It consists of If a raw material compound represented by the general formula [] is used as an optically active substance if necessary, the compound represented by the general formula [] can be synthesized as an optically active substance. As a method for obtaining the optically active compound represented by the general formula [], it is possible to obtain the compound represented by the general formula [] by optical resolution, or the compound represented by the formula (4) can be obtained in advance. After obtaining the optically active form of the compound represented by formula (4) by optical resolution, the optically active general formula is obtained from the optically active compound represented by formula (4) in the same manner as shown in reaction formula [A]. It is also possible to lead to the compounds shown in [ ]. In addition, in this specification, a lower alkyl group means a C1-C3 alkyl group. Further, the term "lower halogenoalkyl group" means an alkyl group having 1 to 3 carbon atoms and substituted with 1 to 3 halogen atoms. Halogen atoms are fluorine, chlorine,
Or it means a bromine atom. Specifically, the compounds included in the present invention are:
For example: 9-acetyl-9-acetamino-6,11-dihydroxy-7,8,9,10-tetrahydro-
5,12-naphthacenedione 9-acetamino-9-(1-ethylenedioxy)ethyl-6,11-dihydroxy-7,8,
9,10-tetrahydro-5,12-naphthacenedione 9-acetyl-6,11-dihydroxy-7,
8,9,10-tetrahydro-7,9-(1-oxa-3-aza-2-methyl-2-propeno)naphthacene-5,12-dione 9-(1-ethylenedioxy)ethyl-6,11
-dihydroxy-7,8,9,10-tetrahydro-7,9-(1-oxa-3-aza-2-methyl-2-propeno)naphthacene-2,12-dione 9-amino-9-acetyl-6 ,7,11-trihydroxy-7,8,9,10-tetrahydro-
5,12-naphthacenedione 9-acetyl-9-acetamino-6,7,11
-Trihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione 9-acetyl-9-trifluoroacetamino-6,7,11-trihydroxy-7,8,9,10
-Tetrahydro-5,12-naphthacenedione 9-
Acetyl-9-acetamino-6,7,11-triacetoxy-7,8,9,10-tetrahydro-
5,12-Naphthacenedione A detailed explanation will be given below with reference to examples and examples, but the present invention is not limited thereto. Reference example 1 1,4-dimethoxy-6-tetralone 82.4g
Add 1200ml of water and 100ml of ethyl alcohol to
Next, 345.6g of ammonium carbonate and potassium cyanide
34.0 g was added and refluxed for 1 hour while stirring. After distilling off the ethyl alcohol under reduced pressure, it was left at room temperature overnight, then cooled in ice water for 2.5 hours, and the precipitated crystals were collected by filtration.
5,8-dimethoxynaphthalene-2,4'-hydantoin] was obtained. mp274-276℃. 3000 ml of water and 630 g of barium hydroxide octahydrate were added to 102.5 g of the above hydantoin and refluxed under a nitrogen stream for 36 hours. Cool to room temperature and add water to the reaction mixture.
After adding 1000ml, add 6N-sulfuric acid at room temperature,
The pH was set to 0.6. Heat to 40-45℃ and apply Celite 300
After stirring for 30 minutes, insoluble matter was filtered off. After adjusting the mother liquor to pH≒6.0 with diethylamine, it was cooled with ice water for 2 hours, and the precipitated crystals were collected by filtration to obtain 2-amino-1,2,3,4-tetrahydro-
5,8-dimethoxy-2-naphthoic acid was obtained.
mp264-266℃ Aminonaphthoic acid derivative obtained from the above reaction 46.5
900 ml of anhydrous pyridine and 90 g of acetic anhydride were added to the mixture, and the mixture was stirred at room temperature overnight. After pyridine was distilled off under reduced pressure, 700 ml of 3% hydrochloric acid was added and stirred at room temperature for 3 hours. The precipitated crystals are collected by filtration and 2-acetamino-
1,2,3,4,-tetrahydro-5,8-dimethoxy-2-naphthoic acid was obtained. mp282―
284℃ IR (Nujol) ν (cm ^-1 ): 3440, 1715, 1620,
1550, 1260, 1110, 1080, 900 Add 2000 ml of anhydrous methanol and 10 ml of concentrated sulfuric acid to 50.0 g of the acetaminonaphthoic acid derivative obtained in the above reaction.
was added and refluxed for 1 hour. Methanol was distilled off under reduced pressure, the residue was poured into saturated aqueous sodium bicarbonate solution, and after stirring for 1 hour, the precipitated crystals were collected by filtration to give 2-acetamino-1,2,3,
4,-tetrahydro-5,8-dimethoxy-2
-Naphthoic acid methyl ester was obtained. mp160―
162℃ Add 48.0g of the above ester to a dimethylsulfoxide solution of methylsulfinyl carbanion prepared from 16g of 65% NaH and 200ml of dimethylsulfoxide and cooled to 3 to 10℃ using a conventional method and add 48.0g of the above ester to 500ml of tetrahydrofuran. The dissolved solution was added dropwise. After dropping, stir at room temperature for 1.5 hours, pour the reaction solution into ice water, and add concentrated hydrochloric acid.
The pH was adjusted to 3.5, and the mixture was extracted with chloroform. The chloroform layer was washed with water, dried over magnesium sulfate, and then the solvent was concentrated under reduced pressure. The precipitated crystals were collected by filtration and 2-acetamino-2-(2-methylsulfinyl-1-oxo)ethyl-1,2,
3,4-tetrahydro-5,8-dimethoxynaphthalene was obtained. mp203-204°C -1 After dissolving 36.2 g of the above naphthalene derivative in 1400 ml of tetrahydrofuran and 1400 ml of water, an aluminum amalgam prepared from 16 g of aluminum foil and 2% HgCl ₂ 3 by a conventional method was added at room temperature. After reacting at room temperature for 30 minutes, insoluble matter was filtered off, and the solvent was distilled off under reduced pressure to obtain 2-acetyl-2-acetamino-1,2,3,4-tetrahydro-
5,8-dimethoxynaphthalene was obtained. mp220
-222℃ IR (Nujol) ν (cm ^-1 ): 3260, 1715, 1640,
1550, 1260, 1100, 1085, 790 -2 2-acetamino-2-(2-methylsulfinyl-1-oxo)ethyl-1,2,
3,4-tetrahydro-5,8-dimethoxynaphthalene 7.0g, zinc powder 5.2g, benzene 400ml
and 70 ml of 20% sodium hydroxide solution were added and refluxed for 6 hours. After filtering off insoluble matter, washing with water and drying over magnesium sulfate, the solvent was distilled off to obtain 2-acetyl-2-acetamino-1,2,3,4-tetrahydro-5,8-dimethoxynaphthalene. Ta. mp218-220℃ Reference example 2 Racemic-2-acetamino-1,2,3,4
-After adding 2.5 g of methanol to 30.1 g of tetrahydro-5,8-dimethoxy-2-naphthoic acid,
12.5 g of l-α-phenylethylamine was added, refluxed, and left overnight at room temperature. The precipitated crystals were collected by filtration to obtain 13.4 g of salt. Add this salt to methanol
Recrystallized from 1.9 to l-2-acetamino-
1,2,3,4-tetrahydro-5,8-dimethoxy-2-naphthoic acid/l-α-phenylethylamine salt 11.8g, mp280℃ or higher, [α] ²⁰ _D −
61.6° (c=0.32, DMF) was obtained. 11.7g of this salt
After adding 800 ml of 3% hydrochloric acid and stirring at room temperature for 1 hour, the precipitated crystals were collected by filtration and l-2-acetamino-1,2,3,4-tetrahydro-5,8-
Dimethoxy-2-naphthoic acid 7.7g, mp280℃
As described above, [α] ²⁰ _D −69.6° (c=1.0, DMF) was obtained. The above salt-precipitated mother liquor and recrystallized mother liquor were combined, methanol was distilled off under reduced pressure, and 1 part of 3% hydrochloric acid was added to the residue, followed by stirring at room temperature for 2 hours. Collect the precipitated crystals by filtration to obtain 2-acetamino-1,2,3,4-tetrahydro-5,8- containing a large amount of d-isomer.
19.0 g of dimethoxy-2-naphthoic acid was obtained, and 900 ml of methanol and 9.0 g of d-α-phenylethylamine were added to the crystals, refluxed, and left at room temperature for 6 hours. The precipitated crystals were collected by filtration to obtain 14.5 g of salt. This salt was recrystallized from methanol 1.5 g to give 7.8 g of d-2-acetamino-1,2,3,4-tetrahydro-5,8-dimethoxy-2-naphthoic acid d-α-phenylethylamine salt.
mp280°C or higher, [α] ²⁰ _D +60.1° (c=0.30, DMF)
I got it. Add 500 ml of 3% hydrochloric acid to 7.5 g of this salt, stir at room temperature for 1 hour, collect the precipitated crystals by filtration, and d-
2-acetamino-1,2,3,4-tetrahydro-5,8-dimethoxy-2-naphthoic acid
5.3g, mp280℃ or higher, [α] ²⁰ _D +68.8゜(c=0.98,
DMF) was obtained. -1 l-2-acetamino-1,2,3,4
-Tetrahydro-5,8-dimethoxy-2-naphthoic acid 10.8g ([α] ²⁰ _D -70.2° (c=1.0,
430 ml of anhydrous methanol and 2 ml of concentrated sulfuric acid in DMF))
was added and refluxed for 1.5 hours. Methanol was distilled off under reduced pressure, and the residue was poured into saturated aqueous sodium bicarbonate solution and stirred for 1 hour. The precipitated crystals were collected by filtration, and l-2-acetamino-1,
2,3,4-tetrahydro-5,8-dimethoxy-2-naphthoic acid methyl ester was obtained.
mp169-170℃, [α] ²⁰ _D -114.5° (c = 1.0, chloroform) -2 d-acetamino-1,2,3,4-tetrahydro-5,8-dimethoxy-2-naphthoic acid ([α] ²⁰ _D +69.4゜(c=1.0, DMF)) 14.5g
d-2-acetamino-1,2,3,4-tetrahydro-
5,8-dimethoxy-2-naphthoic acid methyl ester was obtained. mp169-170℃, [α] ²⁰ _D +113.2゜ (c=1.0, chloroform) -1 l-2-acetamino-1,2,3,4
-Tetrahydro-5,8-dimethoxy-2-naphthoic acid methyl ester ([α] ²⁰ _D -114.5° (c=
A solution prepared by dissolving 10.2 g of 1.0, chloroform) in 120 ml of tetrahydrofuran was diluted with 60
The mixture was added dropwise to a dimethyl sulfoxide solution of methyl sulfinyl carbanion prepared from 4 g of % NaH and 50 ml of dimethyl sulfoxide while cooling at 3 to 10°C. After the dropwise addition, the reaction solution was stirred at room temperature for 1 hour, poured into ice water, adjusted to pH≒3.1 with concentrated hydrochloric acid, and extracted with chloroform. The chloroform layer was washed with water, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, benzene was added to the precipitated crystals, and the crystals were collected by filtration.
-acetamino-2-(2-methylsulfophinyl-1-oxo)ethyl-1,2,3,4-
Tetrahydro-5,8-dimethoxynaphthalene was obtained. mp186-189℃, [α] ²⁰ _D -65.5゜(c=
1.0, chloroform) -2 d-2-acetamino-1,2,3,4
-Tetrahydro-5,8-dimethoxy-2-naphthoic acid methyl ester ([α] ²⁰ _D +113.2° (c=
1.0, chloroform)) Using 13.0g of the above-1
Perform the same reaction as d-2-acetamino-
1-(2-methylsulfinyl-1-oxo)
Ethyl-1,2,3,4-tetrahydro-5,
8-dimethoxynaphthalene was obtained. mp190~
193℃, [α] ²⁰ _D +66.1° (c = 1.1, chloroform) -1 l-2-acetamino-2-(2-methylsulfinyl-1-oxo)ethyl-1,
After dissolving 9.1 g of 2,3,4-tetrahydro-5,8-dimethoxynaphthalene ([α] ²⁰ _D -65.5° (c = 1.0, chloroform)) in 500 ml of tetrahydrofuran and 50 ml of water, aluminum foil 7 was prepared using a conventional method.
An aluminum amalgam prepared from 1.5 g, 2% HgCl ₂ was added at room temperature. 30 at room temperature
After reacting for a minute, insoluble materials were filtered off and the solvent was distilled off under reduced pressure to obtain l-2-acetyl-2-acetamino-1,2,3,4-tetrahydro-5,8-dimethoxynaphthalene. mp227~228℃,
[α] ²⁰ _D -131.2゜(c=1.0, chloroform) -2 d-2-acetamino-2-(2-methylsulfinyl-1-oxo)ethyl-1,
Using 12.0 g of 2,3,4-tetrahydro-5,8-dimethoxynaphthalene [α] ²⁰ _D +66.1° (c = 1.0, chloroform), react in the same manner as in -1 above to form d-2- Acetyl-2-acetamino-1,2,3,4-tetrahydro-5,8-
Dimethoxynaphthalene was obtained. mp225~226℃,
[α] ²⁰ _D +134.2° (c=1.0, chloroform) Example 1 2-acetyl-2-acetamino-1,2,
Thoroughly grind and mix 2.8 g of 3,4-tetrahydro-5,8-dimethoxynaphthalene, 3.4 g of phthalic anhydride, 40 g of aluminum chloride, and 8 g of sodium chloride, and place the mixture in an eggplant-shaped flask preheated to 180℃. Add at once to 180℃
Continued heating. After melting and reacting for 2 minutes,
The reactants were added to 500 ml of a saturated oxalic acid solution that was rapidly cooled to room temperature and then cooled with ice water. After stirring at room temperature for 10 minutes, the precipitated crystals were collected by filtration and 9-acetyl-9-
acetamino-6,11-dihydroxy-7,8,
9,10-tetrahydro-5,12-naphthacenedione was obtained. mp295-303℃ (decomposition). IR (Nujol) ν (cm ^-1 ): 3340, 1710, 1660,
1620, 1590, 1530, 1260, 1120,
1040,970 Example 2 9-acetyl-9-acetamino-6,11-dihydroxy-7,8,9,10-tetrahydro-
8.0g of 5,12-naphthacenedione and anhydrous toluene
1,600 ml, 34 ml of ethylene glycol, and 1.6 g of p-toluenesulfonic acid were added, and the mixture was reacted for 5 and a half hours while removing azeotropic water under reflux. The reaction solution was decanted to remove tar, and then concentrated under reduced pressure to about 100 ml. The precipitated crystals were collected by filtration to obtain 9-acetamino-9-(1-ethylenedioxy)ethyl-6,11-dihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione.
mp273―275℃ IR (Nujol) ν (cm ^-1 ): 3260, 1650, 1610,
1580, 1280, 1250, 1140, 810 Example 3 9-acetamino-9-(1-ethylenedioxy)ethyl-6,11-dihydroxy-7,
1.66 g of 8,9,10-tetrahydro-5,12-naphthacenedione was dissolved in 50 ml of chloroform and 180 ml of carbon tetrachloride under reflux, then 1.35 g of N-bromosuccinimide was added and irradiated with a 500 W visible light lamp. The mixture was refluxed for 15 minutes. After cooling with ice water for 1 hour, the precipitate was collected by filtration. The precipitate was dissolved in chloroform, washed successively with saturated sodium bicarbonate solution, 5% sodium thiosulfate, and water, and then dried over magnesium sulfate. After distilling off the solvent, it was crystallized with isopropyl ether to give 9-(1-ethylenedioxy)ethyl-6,11 dihydroxy-7,8,9,10-
Tetrahydro-7,9-(1-oxa-3-aza-2-methyl-2-propeno)naphthacene-
5,12-dione was obtained. mp191―195℃ IR (Nujol) ν (cm ^-1 ): 1660, 1640, 1590,
1260, 1220, 1200, 1170, 1040, 970 9-(1-ethylenedioxy)ethyl-6,
11-dihydroxy-7,8,9,10-tetrahydro-7,9-(1-oxa-3-aza-2-
Methyl-2-propeno)naphthacene-5,12-
24 ml of dioxane, 24 ml of water and 6 ml of concentrated hydrochloric acid were added to 1.24 g of dione, and the mixture was refluxed for 13 hours. The residue obtained by distilling off the solvent under reduced pressure was dissolved in 30 ml of methanol, and then 200 mg of activated carbon was added and stirred. After filtering off insoluble matters, the resulting residue was concentrated under reduced pressure and crystallized from isopropyl alcohol to give 9-amino-9-acetyl-6,7,11-trihydroxy-7,
8,9,10-tetrahydro-5,12-naphthacenedione hydrochloride was obtained. mp218―223℃ IR (Nujol) ν (cm ^-1 ): 3400, 1720, 1620,
1590, 1260, 1160, 1120, 990 Example 4 9-acetyl-9-acetamino-6,11-
200 mg of dihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione was dissolved in 200 ml of anhydrous chloroform under reflux, and then 100 mg of N-bromosuccinimide was added and the solution was dissolved under reflux while irradiating with a 500 W visible light lamp. Refluxed for minutes. After cooling,
Saturated sodium bicarbonate solution was added and the mixture was separated into a chloroform layer. The chloroform layer was washed successively with 5% thiosulfuric acid solution and water, and dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by chromatography to obtain 9-acetyl-6,11-dihydroxy-
7,8,9,10-tetrahydro-7,9-(1
-oxa-3-aza-2-methyl-2-propeno)naphthacene-5,12-dione was obtained.
mp200―204℃ IR (Nujol) ν (cm ^-1 ): 1720, 1670, 1620,
1590, 1250, 1210, 1050, 970 9-acetyl-6,11-dihydroxy-7,
8,9,10-tetrahydro-7,9-(1-oxa-3-aza-2-methyl-2-propeno)
4 ml of dioxane, 4 ml of water and 1 ml of concentrated hydrochloric acid were added to 61 mg of naphthacene-5,12-dione and heated at 90-100°C for 3 hours. After the reaction was distilled off under reduced pressure, 9
-amino-9-acetyl-6,7,11-trihydroxy-7,8,9,10-tetrahydro-
5,12-naphthacenedione hydrochloride was obtained.
mp210―215℃ IR (Nujol) ν (cm ^-1 ): 3400, 1720, 1620,
1590, 1260, 1160, 1120, 990 Example 5 9-amino-9-acetyl-6,7,11-trihydroxy-7,8,9,10-tetrahydro-
130mg of 5,12-naphthacenedione hydrochloride, 400mg of soda carbonate, 20ml of saturated sodium bicarbonate solution and 10ml of chloroform
ml and 10 ml of tetrahydrofuran were added thereto, and 200 mg of acetyl chloride was slowly added dropwise at room temperature while stirring vigorously. After the dropwise addition, the mixture was stirred for 30 minutes, 50 ml of chloroform was added, the chloroform layer was separated, washed with water, dried over magnesium sulfate, the solvent was distilled off, and the resulting residue was crystallized from diethyl ether to give 9-acetyl-
9-acetamino-6,7,11-trihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione was obtained. mp240~245℃ IR (Nujol) ν (cm ^-1 ): 3300, 1710, 1650,
1620, 1590, 1250, 1030, 980 Example 6 9-amino-9-acetyl-6,7,11-trihydroxy-7,8,9,10-tetrahydro-
130 mg of 5,12-naphthacenedione hydrochloride was dissolved in 10 ml of methylene chloride and 1 ml of pyridine, and 300 mg of trifluoroacetic anhydride was slowly added dropwise while stirring at room temperature. After dropping, the mixture was reacted for 1 hour, and the reaction solution was poured into 3% hydrochloric acid and extracted with chloroform.The chloroform layer was washed successively with water, saturated aqueous sodium bicarbonate, and water, and dried over magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography to obtain 9-acetyl-9-trifluoroacetamino-6,7,11-trihydroxy-7,8,9,
10-tetrahydro-5,12-naphthacenedione was obtained. mp218~221℃ IR (Nujol) ν (cm ^-1 ): 3300, 1710, 1620,
1590, 1260, 1200, 1140 Example 7 9-amino-9-acetyl-6,7,11-trihydroxy-7,8,9,10-tetrahydro-
10 ml of anhydrous pyridine was added to 550 mg of 5,12-naphthacenedione hydrochloride, 3 ml of acetic anhydride was added under cooling with ice water, and the mixture was heated at 60 to 65° C. for 30 minutes. The reaction solution was poured into 3% hydrochloric acid, extracted with chloroform, washed sequentially with water, saturated sodium bicarbonate solution, and water.
It was dried with magnesium sulfate. The residue obtained by distilling off the solvent was purified by chromatography,
9-acetyl-9-acetamino-6,7,11-
Triacetoxy-7,8,9,10-tetrahydro-5,12-naphthacenedione was obtained. mp276～
278℃ IR (Nujol) ν (cm ^-1 ): 3450, 1770, 1740,
1720, 1680, 1590, 1260, 1230,
1190, 1020 Example 8 (a) l-2-acetyl-2-acetamino-1,
2,3,4-tetrahydro-5,8-dimethoxynaphthalene 2.8 g ([α] ²⁰ _D -131.2° (c = 1.0,
Thoroughly grind and mix together chloroform)), 3.4 g of phthalic anhydride, 40 g of aluminum chloride, and 8 g of sodium chloride.
It was added all at once into an eggplant-shaped flask that had been heated to 180°C, and heating was continued at 180°C. After melting and reacting for 2 minutes, the reaction product was rapidly cooled to room temperature, and then added to 500 ml of a saturated oxalic acid solution cooled with ice water. After stirring at room temperature for 10 minutes, the precipitated crystals were collected by filtration.
l-9-acetyl-9-acetamino-6,11
-dihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione was obtained. mp300
℃ or more IR (Nujol) ν (cm ^-1 ): 3340, 1705, 1670,
1620, 1585, 1520, 1250, 1110,
1040,970 [α] ²⁰ _D −85° (c=0.05, DMF) (b) d-2-acetyl-2-acetamino-1,
2,3,4-tetrahydro-5,8-dimethoxynaphthalene 2.8 g ([α] ²⁰ _D +132.2° (c = 1.0,
A reaction was carried out in the same manner as in Example 8(a) using chloroform)), 3.4 g of phthalic anhydride, and 40 g of aluminum chloride to obtain d-9-acetyl-9-acetamino-6,11-dihydroxy-7,8,9, 10-tetrahydro-5,12-naphthacenedione was obtained. mp300℃ or higher IR (Nujol) ν (cm ^-1 ): 3340, 1705, 1670,
1620, 1585, 1520, 1250, 1110,
1040,970 [α] ²⁰ _D +90° (c=0.07, DMF) Example 9 (a) l-9-acetyl-9-acetamino-6,
6.38 g of 11-dihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione, 1400 ml of anhydrous toluene, 23 ml of ethylene glycol and p
- 1.1 g of toluenesulfonic acid was added, and the mixture was allowed to react for 5 and a half hours while removing azeotropic water under reflux. After pouring the reaction solution into 1 1 of saturated aqueous sodium bicarbonate solution, the toluene layer was separated, washed with water, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to about 100 ml. The precipitated crystals were collected by filtration, and l-9-acetamino-
9-(1-ethylenedioxy)ethyl-6,11
-dihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione was obtained. mp259
-262℃ (decomposition) IR (Nujol) ν (cm ^-1 ): 3260, 1660, 1610,
1580, 1280, 1250, 1200, 1140, 810,
790 [α] ²⁰ _D −308° (c=0.23, chloroform) (b) d-9-acetyl-9-acetamino-6,
The same reaction as in Example 9(a) was carried out using 5.6 g of 11-dihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione to obtain d-9-acetamino-9-(1- Ethylenedioxy)ethyl-6,11-dihydroxy-7,8,9,10
-Tetrahydro-5,12-naphthacenedione
The hydrochloride was obtained. mp260~263℃ (decomposition) IR (Nujol) ν (cm ^-1 ): 3260, 1660, 1610,
1580, 1280, 1250, 1200, 1140, 810,
790 [α] ²⁰ _D +310℃ (c=0.23, DMF) Example 10 (a) - l-9-acetamino-9-(1-ethylenedioxy)ethyl-6,11-dihydroxy-7,8,9 , 5.56 g of 10-tetrahydro-5,12-naphthacenedione was dissolved in 160 ml of chloroform and 700 ml of carbon tetrachloride under reflux, and then 4.53 g of N-bromosuccinimide was added and the mixture was irradiated with a 500 W visible light lamp for 20 minutes. It refluxed. After cooling with ice water for 1 hour, the precipitate was collected by filtration. The precipitate was dissolved in chloroform, washed successively with saturated sodium bicarbonate solution, 5% sodium thiosulfate, and water, and then dried over magnesium sulfate. After distilling off the solvent, it was crystallized with isopropyl ether to give d-9-(1-ethylenedioxy)ethyl-6,11-dihydroxy-7,
8,9,10-tetrahydro-7,9-(1-oxa-3-aza-2-methyl-2-propeno)
Naphthacene-5,12-dione was obtained. mp160～
165℃ IR (Nujol) ν (cm ^-1 ): 1660, 1620, 1580,
1270, 1230, 1200, 1100, 1030, 970 [α] ²⁰ _D +376.3℃ (c=0.22, chloroform) (a)- d-9-(1-ethylenedioxy)ethyl-6,11-dihydroxy- 7, 8, 9, 10-
Tetrahydro-7,9-(1-oxa-3-aza-2-methyl-2-propeno)naphthacene-
4.35g of 5,12-dione, 70ml of dioxane, 70ml of water
ml and 18 ml of concentrated hydrochloric acid were added and refluxed for 15 hours. The residue obtained by distilling off the solvent under reduced pressure was dissolved in 400 ml of methanol, and then 350 mg of activated carbon was added and stirred. After filtering off insoluble materials, the resulting residue was concentrated under reduced pressure and crystallized from isopropyl alcohol to give l-9-amino-9-acetyl-6,7,11-trihydroxy-7,8,9,10 -Tetrahydro-5,12
- Obtained naphthacenedione hydrochloride. mp224～
230℃ IR (Nujol) ν (cm ^-1 ): 3400, 1720, 1620,
1590, 1260, 1240, 1160, 1130,
1000,970 [α] ²⁰ _D −89° (c=0.1, DMP) (b)— d-9-acetamino-9-(1-ethylenedioxy)ethyl-6,11-dihydroxy-7,8,9 , 10-tetrahydro-5,12-naphthacenedione was reacted in the same manner as in Example 10(a) to obtain l-9-(1-ethylenedioxy)ethyl-6,11-dihydroxy-7,8. ，
9,10-tetrahydro-7,9-(1-oxa-3-aza-2-methyl-2-propeno)naphthacene-5,12-dione was obtained. mp158~163
℃ IR (Nujol) ν (cm ^-1 ): 1660, 1620, 1580,
1270, 1230, 1200, 1100, 1030, 970 [α] ²⁰ _D -354° (c = 0.21, chloroform) (b) - l-9-(1-ethylenedioxy)ethyl-6,11-dihydroxy-7 ,8,9,10-
Tetrahydro-7,9-(1-oxa-3-aza-2-methyl-2-propeno)naphthacene-
Using 5,12-dione, the reaction was carried out in the same manner as in Example 10(a) to obtain d-9-amino-9-acetyl-
6,7,11-trihydroxy-7,8,9,10
-Tetrahydro-5,12-naphthacenedione
The hydrochloride was obtained. mp224~230℃ IR (Nujol) ν (cm ^-1 ): 3400, 1720, 1620,
1590, 1260, 1240, 1160, 1130,
1000,970 [α] ²⁰ _D +94° (c=0.09, DMF) Example 11 l-9-amino-9-acetyl-6,7,11-
130 mg of trihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione hydrochloride was dissolved in 10 ml of methylene chloride and 1 ml of pyridine, and 300 mg of trifluoroacetic anhydride was slowly added dropwise under stirring at room temperature. . After dropping, react for 1 hour, and reduce the reaction solution to 3%
After pouring into aqueous hydrochloric acid and extracting with chloroform, the chloroform layer was sequentially washed with water, saturated aqueous sodium bicarbonate, and water.
Dry with magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography to obtain d-9-acetyl-9-trifluoroacetamino-6,7,11-trihydroxy-7,8,
9,10-tetrahydro-5,12-naphthacenedione was obtained. mp236~238℃ IR (Nujol) ν (cm ^-1 ): 3500, 3300, 1720,
1620, 1590, 1540, 1240, 1210,
1160,990 [α] ²⁰ _D +207° (c=0.2, chloroform) Example 12 l-2-acetyl-2-trifluoroacetamino-1,2,3,4-tetrahydro-5,8-
Dimethoxynaphthalene 2.8g ([α] ²⁰ _D −117.3゜(c
=0.26, chloroform)), phthalic anhydride 3.4g,
Thoroughly grind 40g of aluminum chloride and 8g of sodium chloride and mix them together.
It was added all at once into an eggplant-shaped flask that had been heated to 180°C, and heating was continued at 180°C. After melting and reacting for 2 minutes, the reaction product was rapidly cooled to room temperature and then added to 500 ml of a saturated oxalic acid solution cooled with ice water. After stirring at room temperature for 10 minutes, the precipitated crystals were collected by filtration and
acetyl-9-trifluoroacetamino-6,
11-dihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione was obtained. Melting point:
289℃ (decomposition) IR (Nujol) ν (cm ^-1 ): 3300―3600, 1738,
1772, 1630, 1598 [α] ²⁰ _D −115° (c=0.05, CHCl ₃ )

Claims (1)

[Claims] 1. General formula [In the formula, R ₁ means a hydrogen atom or -COR ₇ . R ₂ and R ₃ together mean an ethylenedioxy group or an oxo group. R ₄ and R ₅ both represent a hydrogen atom, or one represents a hydrogen atom and the other represents -COR ₇ . R ₆ is a hydrogen atom,
means hydroxy group or -OCOR ₇ . R ₇ means a lower alkyl group or a lower halogenoalkyl group. ] An aminonaphthacene derivative represented by 2 General formula [In the formula, R ₇ means a lower alkyl group or a lower halogenoalkyl group. ] A general formula characterized by reacting a compound represented by with phthalic anhydride in the presence of a Lewis acid. [In the formula, R ₇ has the same meaning as above. ] A method for producing an aminonaphthacene derivative represented by 3 General formula [In the formula, R ₂ and R ₃ together mean an ethylenedioxy group or an oxo group, and R ₇ means a lower alkyl group or a lower halogenoalkyl group. ] A formula characterized by hydrolyzing a compound represented by A method for producing an aminonaphthacene derivative represented by 4 General formula A compound represented by the general formula R ₇ COOH [wherein R ₇ means a lower alkyl group or a lower halogenoalkyl group]. ] A general formula characterized by condensation with the compound represented by or its reactive derivative [In the formula, R ₁ means a hydrogen atom or -COR ₇ . R ₇ has the same meaning as above. ] A method for producing an aminonaphthacene derivative represented by