JPS62132838A - Production of tetrahydronaphthacene derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a synthetic intermediate having remarkable carcinostatic activity, in one step and high yield under mild condition, by using a specific compound and phthaloyl dichloride as raw materials and reacting the materials in the presence of a Lewis acid catalyst. CONSTITUTION:The objective compound of formula III can be produced by reacting the compound of formula I [R<1> is acetyl or lower alkoxycarbonyl; R<2> is OR<3> (R<3> is H or OH-protecting group), NHCOR<4> (R<4> is lower alkyl or lower halogenoalkyl) or group of formula II (X is H or halogen)] with phthaloyl dichloride in a solvent such as dried dichloroethane in the presence of a Lewis acid such as AlCl3 at room temperature for 2-16hr. EFFECT:The objective compound can be produced in high optical purity on an industrial scale without causing racemization of the product. USE:A synthetic intermediate for 4-demethoxydaunomycin or 4-deme thoxyadriamycin which are anthracycline-type antibiotic substances of non-natu ral origin and having remarkable carcinostatic activity.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel and industrial method for producing tetrahydronaphthacene derivatives.

More specifically, the general formula [[] CH3 [wherein, R means an acetyl group or a lower alkoxycarbonyl group, R2 (dOR3 (R3 means a protecting group for a hydrogen atom or hydroxyl group)] or NHCOR' (R
4 means a lower alkyl group, LOW means a hydrogen atom, and MINEN means a halogen atom. ) means. ) means. ] General formula CII, characterized in that the compound represented by the following is reacted with phthalic acid dichloride in the presence of M isic acid] OH [wherein R1 and R2 have the same meanings as above. ] The present invention relates to a method for producing a tetrahydronaphthacene derivative shown in the following.

(b) Industrial application field Among the compounds [■] produced according to the present invention, 9-hydroxytetrahydrophthacene derivative (IIa) in which R2 is a hydroxy substituent (OR') has a remarkable anticancer effect. As a synthetic intermediate for 4-demethoxydaunomycin [out, R5=H] or 4-demethoxyadriamycin [[[I, R=OH]], which is a non-natural anthracycline antibiotic that has attracted particular attention in recent years. It is extremely useful.

That is, 9- in which R is OR8 in the general formula [■]
Hydroxytetrahydronaphthacene derivative (I[a]
can be easily converted to the aglycone 4-demethoxydaunomycinone [■] according to methods known in the literature.

Then, by reacting the compound [■v] with a daunosamine derivative, 4-demethoxydaunomycin'm, R
5=H), and further compound Cm, R6=H"J
CF, Alcamone, -Doxorubici can be converted to 4-demethoxyadriamycin [m, R5=OH1 by introducing a hydroxyl group to the C-14 position of
n' AcademicPress: New Yo
rk, 19811゜Also, in the compound [■] produced according to the present invention, R is an amide substituent (NHCOR)
9-amidetetrahydronaphthacene derivative [■b
], like the above-mentioned 9-hydroxytetrahydronaphthacene derivative (lla), is an extremely useful intermediate for the synthesis of compound [V], which is one of the non-natural anthracycline antibiotics that has a remarkable anticancer effect. It is useful.

That is, the 9-amidotetrahydronaphthacene derivative (nbl) obtained in the present invention can be easily converted into an aglycone [vI] by a known method, and can be further converted into 9-aminoanthracycline [vh] by reacting with a Tong derivative. [Unpublished patent publication: 1982-29750, 1982
-194846, 1984-76099, 1986-7
No. 5478].

(b) Conventional technology The aglycon moiety of anthracycline antibiotics has a basic skeleton of a tetofhydronaphthacene derivative [■], and its synthesis is (1) A method using F1-Del and Claff reactions as the basic steps. , (2) A method using Diyas and Anoredar reactions as the basic steps, and (8) A method using 1, 2 and 1,4-addition reactions as the basic steps. Among them, the method using the Friede M and Kraf reaction as the basic step uses 4-demethoxy anthracyclinone ([■] or [VO
), etc., and for example, two methods shown in Reaction Formulas 1 and 2 are known.

Reaction Formula 1 %Formula % [In the formula, R6 means a methyl group, an ethyl group, or a herogen-substituted ethyl group. ] That is, the synthesis method shown in Reaction Formula 1 is based on 2-acetyl-2
-hydroxy-1,2,8,4-tetrahydro-5,8
-Dimethoxynaphthalene 2 and phthalic acid heptanoester M monochloride are mixed with organic PatJ such as dichloromethane.
Compound 8 was obtained by reacting in the presence of a Lewis acid such as anhydrous aluminum chloride in X, and hydroxylated. , and further demethylated using an I-reiss acid such as anhydrous aluminum chloride to obtain tetrahydro-
This is a method for obtaining naphthacene derivative 6 [published patent publication:
No. 51-98264: F, a! Lecamone et al., Canc.
er Treatment Reports, 60
, 829 (1976) 1° Reaction formula 2 ○ OH9 0 means a gene atom. ) means. ) means.

] That is, the synthesis method shown in Reaction Formula 2 involves combining tetrahydronaphthalene derivative 8 and phthalic anhydride 7 at 180° C. in the presence of sodium chloride and anhydrous aluminum chloride.
This is a method for obtaining tetrahydronaphthacene derivative 9 by melting reaction for a minute [Publication Patent Publication: 1983-15]
No. 852, No. 58-29750, No. 58-19484
No. 6; F, Alcamone et al.

Experience, 84, 1255 (197
8)].

(c) Problems to be Solved by the Invention The synthesis method shown in reaction formula 1 requires as many as four long reaction steps to obtain the desired tetrahydronaphthacene derivative 6, and the overall yield is low. It is low at about 60%. Furthermore, hydrofluoric acid is used in the Friedel-Craf ring closure reaction from compound 4 to compound 5, and it cannot be said that this is an industrial method for producing tetrahydronaphthacene derivative 6.

In addition, in the synthesis method shown in Reaction Formula 2, the desired tetrahydronaphthacene derivative can be obtained in one step, and the yield is about 70% to 90%. The reaction conditions are severe: 180° C. for 2 minutes, and it is known that if the reaction time is increased at the same temperature, the by-products of decomposition products such as Compound 10 (OH) will significantly increase. Therefore, this synthetic method also has problems as an industrial method for producing tetrahydronaphthacene derivative 9.

Furthermore, when the C-2 position of the tetrahydronaphthalene derivative [■] used in either method of Reaction Formulas 1 and 2 is a hydroxy group or its protected form, this product can be used as an optically active form. However, racemization partially progresses during the reaction, and only a tetrahydronaphthacene derivative [■] with an optical purity of 70-80% is obtained, and the obtained tetrahydronaphthacene derivative with an optical purity of 70-75% has a volume of 8. It is known that it cannot be made into an optically pure product, and that it can only be obtained as a pure product with a yield of about 40% at most by repeated recrystallization [Terajima JEbe et al. Chem, Pharm.

Bull, 31811 (1983); Tetrah
edronLevers.

2589 (1983) 1° Incidentally, it is known that when the C-2 position of a tetrahydronaphthacene derivative is an amino substituent, racemization does not occur at all.

As mentioned above, in both of the methods shown in reaction formulas 1 and 2, the reaction conditions are harsh for industrial production methods, and furthermore, because of the harshness, when R2 is a hydroxy group, etc. However, there is a problem with racemization in some parts.

B) Means for Solving the Problems Therefore, in order to solve the problems of the prior art, the present inventors discovered that it is possible to synthesize the desired tetrahydronaphthacene derivative in one step, and that it is possible to synthesize the desired tetrahydronaphthacene derivative from phthalic anhydride. Various studies were conducted on this reaction using phthalic acid dichloride, which is expected to undergo ring-closing Friedel and Clach reactions under mild reaction conditions.

Generally, in the Friedel-Crach reaction of phthalic acid dichloride and benzene, as shown in reaction formula 3, the target anthraquinone 11 is hardly obtained, and it is known that phenyl phthalide 12 is produced as the main product. CG, A., Oler et al. -Fr1edel-Cr
aftsand Re1ated Reactive
ns” vol B, John Wiley (1
964)).

Reaction Formula 3 % Formula % However, when the present inventors attempted to react the compound represented by the general formula CI with phthalic acid dichloride in the presence of a Lewis acid, they were surprised to find that the reaction was mild, lasting several hours at room temperature. The inventors have discovered that the desired tetrahydronaphthacene derivative represented by the general formula [■] can be obtained in high yield under the following conditions without any toracemization, and the problems of the prior art have been overcome, and the present invention has been completed. (E) Structure of the Invention In the method of the present invention, a compound represented by the general formula [■] is reacted with a phthalic acid dichloride in a solvent in the presence of a Lewis acid. Tetrahydronaphthacene derivatives can be produced.

I-Reiss acids include common Friedel and Krach reaction catalysts such as aluminum chloride, aluminum bromide, antimony pentachloride, ferric chloride, titanium tetrachloride, and stannic chloride, but they are easy to obtain and handle. The use of aluminum chloride is preferred. There is no particular restriction on the amount of Lewis acid used, but it is sufficient to use it in an amount of 2 to 10 times the mole of the compound ('r), usually 5 to 10 times the amount of the compound ('r).

As a reaction solvent, usual Frieda I, solvents used in Clauff reaction, such as nitrobenzene, carbon disulfide, dichloromethane, carbon tetrachloride, 1,2-dichloroethane, etc. can be used, but preferably dichloromethane, carbon tetrachloride, 1,2-dichloroethane, etc. can be used. An alkyl halide solvent such as 2-dichloroethane is used.

There is no particular restriction on the amount of phthaloyl dichloride used, but it is sufficient if it is used in an amount of 1 to 2 times, usually 1 to 1.2 times, the amount of compound [■].

There are no particular restrictions on the reaction temperature and reaction time, but room temperature, 2
A reaction time of ~16 hours is sufficient.

After the completion of the reaction, the reaction product can be isolated by a conventional organic chemical method. When the amide-tetrahydronaphthacene derivative (IIb') is produced according to the method of the present invention, it gives the desired product almost quantitatively, while the general formula [
When producing a 9-hydroxytetrahydronaphthacene derivative ([II], R=OH) in which R is a hydroxy group in the general formula [■] according to the method of the present invention, the hydroxy group of R2 in the general formula [■] It is preferable to react using a protected compound (gives the target product in high yield),
If a compound in which R is a hydroxy group is used, the yield will decrease. When a compound in which R2 is an esterified hydroxy group is used as a raw material compound, the above general formula [■]
It is possible to obtain a compound in which R is an esterified hydroxy group, or a mixture of a compound in which R is an esterified hydroxy group and a compound in which R is a hydroxy group. During post-treatment after the completion of the reaction, by stirring for several hours in acidic conditions (e.g. in oxalic acid water), or by alkali treatment after isolation of the product, or by carrying out the Friedel-Krauff reaction for a long time. Deesterification also proceeds easily to give the desired 9-hydroxy-tetrahydronaphthacene derivative ([II), R=OH) in high yield.

The compound represented by the general formula [■] produced by the method of the present invention has a blue carbon, but the present invention includes all stereoisomers, and these isomers can be used as a single substance or as a mixture in the present invention. It constitutes.

The compound represented by the general formula [■] can be produced as an optically active form by using the compound represented by the general formula (T') as an optically active form, if necessary.

When the 9-amide-tetrahydronaphthacene derivative [11b1] in which R is an amide substituent in the general formula CT1 is produced according to the method of the present invention, substantially no racemization occurs and the optical purity is 100%. Give an object.

On the other hand, in the general formula [■], 9-
Hydroxy-tetrahydronaphthacene derivative ([:'I
When ROH) is produced according to the method of the invention, the desired product is obtained with an optical purity of 90% or more, although it is accompanied by some racemization, and this product can be substantially improved to an optical purity of 100% by recrystallizing it once with benzene. % of the object easily.

Here, I would like to mention the terms used in this specification to represent substituents. and t-butyl group 4.

The "lower alkoxycarbonyl group" includes, for example, an alkoxycarbonyl group having 1 to 4 carbon atoms in the after-recording part, and more specifically, a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, and an ethoxycarbonyl group. quincaflebonyl group, impropoquincaflebonyl group, n-ethoxy, tA/honyl group, isoptoxycal levonyl group,
Examples include t-butoxycarbonyl group. "
The "lower halogenoalkyl group" can be, for example, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms.

By halogen atom is meant chlorine or bromine atom. As the "protecting group for hydroxyl group", for example, protecting groups that are generally used for the purpose of protecting hydroxyl group can be applied. Examples of such protecting groups include lower alkanoyl group, lower halogenoalkacyl group, etc. ? Examples include a group, an alloy I group, and the like. Furthermore, ``lower alekanoyl groups include alkyl groups having 1 to 5 carbon atoms such as holemyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, etc. Examples of the "lower halogenoyl lecanoyl group" include a chloroacetyl group, a bromoacetyl group, a cycloacetyl group, a dibromoacetyl group,
Examples of "alloy group" include acetyl groups substituted with 1 to 3 halogen atoms such as trichloroacetyl group, tribromoacetyl group, trifluoroacetyl group, etc., such as hachenzoyl group, p- Nitropency I group, o-Nitropency I group, p-chloropensy I group
Examples thereof include substituted benzoyl groups such as shi group, o-chloropensy group, and the like.

As stated above, the present invention relates to compounds that are important intermediates for the production of non-naturally occurring 4-demethoxy-daunomycin, 4-demethoxyadriamycin, or 9-aminoanthocytalin, etc. The object of the present invention is to provide a novel method that enables industrial production with high yield and high optical purity with almost no racemization.

(f) Examples The present invention will be explained in detail with reference to Examples below, but the present invention is not limited to the following Examples.

Example 1 L-2-acetifure 2-acetamino-1°2.8.
4-tetrahydro-5,8-dimethoxynaphthalene [[
α]6°-181.2°(c=1°cHcz8)](t
o o wq ) and dichloride 7-talate (88,6
Aluminum chloride (229q) was added to the dry dichloroethane (5-) solution of q), and the reaction was stirred at room temperature for 8 hours. After distilling off the solvent, saturated oxalic acid water (4 (it/)
was added and crystallized with stirring. By offshore the precipitated crystals, crude, t-g-acetyl-9-acetamino-
6,11-dihydroxy-7,8゜9.10-tetrahydro-5,12-naphthacenedione [melting point 279-28
8°C, [α]D-118,8° (C=0.05, C
112q of HCL3) 1 was obtained in a yield of 90.4%.

IR (Nujol) ν (cyn), 3840.1
705.1670.

L620.1585.1520 Example 2 t-2-acetyl/l/-2-) ref l leoloamotoamino-1,2,8,4-tetrahydro-5,8-dimethoxynaphthalene [[α]D-117 .8° (c = 0.
26, CHCLs) 1 (690η) tophthalic acid dichloride (460 η) o dry dichloroethane (la
Aluminum chloride (1,83F) was added to the iTnt) solution, and the reaction was stirred at room temperature for 16 hours. After evaporating the solvent, the residue was dissolved in methanol (20, d) and added dropwise to saturated oxalic acid water (20 (lx/)). By scraping off the precipitated crystals, crude t-9-acetyl-9- 870q of trifluoroacetamino-6,11-dihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione [melting point 270-274°C] was obtained in a yield of 97.8%.

The crude product was stirred and washed with ether (5tnt) [melting point 289°C (decomposition), I R (KB r ) v
ccr'>8300-9600.1718.1?20.
1680.1598.

Ca]n 115. l'(c = 0.05, C
HCAa) Mass spectrometry (by field desorption mass spectrometry; the same applies hereinafter) M447] (7
) A purified product was obtained at Cape 752 with a yield of 84.1%.

Example 3 2-acetyl-2-hydroxy-1,2°8.4-tetrahydro-5,8-dimethoxynaphthalene (100%,
! : A solution of dichlorophyte phthalate (97,4η) in dry dichloroethane (5at) was added with aluminum chloride (267
Misaki) was added thereto, and the reaction was stirred at room temperature for 16 hours.

After distilling off the solvent, saturated oxalic acid water (40, II/) was added to the residue, and the precipitated oil was extracted with dichloromethane. The extracted layer was washed with sodium bicarbonate solution and brine, dried over sodium sulfate, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography (
9-acetyl-6,9,11-trihydroxy 7,8 by purification with 1% methanol/methylene chloride)
．． 9.10-Tetrahydro-5゜12-naphthacenedione [melting point 21B-216℃] 8C)q Yield 21.8%
I got it.

Example 4 (R) -2-acetyl-2-hydroxy-1°2.8
．． 4-tetrahydro-5,8-dimethoxynaphthalene [
[α1D-45, 1°Cc=1°CHCL3) = 9
By reacting 7.7%ee) (100-9) in the same manner as in Example-3 and post-treatment, 9(
R)-acetifure6.9゜11-trihydroxy-7
, 27q of 8,9,10-tetrahydro-5,12-naphthacenedione [1 point 215-219°C], yield 19.
Obtained at 2%. The optical rotation of this object is -78.8° (c-'
1, CHCta) with 90% ee was obtained.

Example 5 2-acetyl-2-acetoxy-II2゜3.4-tetrahydro-5,8-dimethoxynaphthalene (50w1)
Aluminum chloride (228η) was added to a solution of phthalic acid chloride (69,5■) in dry dichloroethane (5,d).
was added, and the reaction was stirred at room temperature for 16 hours. After distilling off the solvent, oxalic acid water (40 t/) was added to the residue and crystallized with stirring.

By adding the precipitated crystals, the crude product, 9-acetyl-6,9,
11-trihydroxy-7,8゜9.10-tetrahydro-5,12-naphthacenedione [-points 200-205
℃] was obtained at 46 cape in a yield of 76.8%.

The crude product was purified by silica gel column chromatography (2% methanol/I/methylene chloride) [melting point 2
18-216°C] was obtained in an amount of 41 wq with a yield of 68%.

Example 6 (R) -2-acetyl-2-acetoxy-1°2.3
．． 4-tetrahydro-5,8-dimethoxynaphthalene [
[α) D-45,6° (c=1.0.

CHCL3)'] (100 Misaki) was reacted and post-treated in the same manner as in Example-5 to obtain 9(R).
-acetyl-6,9,11-)rihydroxy 7.8,
54q of 9.10-tetrahydro-5,12-naphthacenedione [melting point 216-218°C] was obtained in a yield of 45%. The optical rotation of this object is -78.8° (c=0.1°C
HCL3) with 90% ee was obtained.

Example 7 (R)-2-acetyl-2-acetoxy-1,,2,
By reacting 3,4-te;-rahydro-5.8-dimethoxynaphthalene (100■)= for 5 hours in the same manner as in Example-5 and post-treatment, 9(R)-acetyl-9- Acetoxy-6,11-dihydroxy-7,8゜9,IO-tetrahydro-5,12-naphthacenedione was obtained in 53 caps, yield 39.3%, [melting point 247-24
9°C, IR(Nujol)y""-1): 1750.
17a0.110.1600[α]20-67.3'(
c = 0.1, CHC2a), mass spectrometry M”8
94] Also, 9(R)-acetyl-6゜9 as a by-product
．． 11-trihydroxy-7,8,9.

, 10-tetrahydro-5,12-naphthacenedione was obtained in an amount of 13 wq and a yield of 10.8%.

Example 8 2-acetoxy-2-carbomethoxy-1°2.3.4
-tetrahydro-5,8-dimethoxynaphthalene (10
0q) Womi example 5. ! = 9-power by reacting in the same manner and post-processing! Levomethoxy-6,9
, LL-trihydroxy-7,8,9,10-tetrahydronaphthacene-5,12-dione total 53 capes, yield 44
．． Obtained at 5%. [Melting point 210-214℃, IR (Nuj
ol)v""" 8500, 8470.

1745.1720.1610.1600 Mass spectrometry +

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 means an acetyl group or lower alkoxycarbonyl group, R^2 means OR^3 (R^3 is a hydrogen atom or a hydroxyl group) ) or NHCO
R^4 {R^4 means a lower alkyl group, a lower halogenoalkyl group, or ▲a numerical formula, a chemical formula, a table, etc.▼ (X means a hydrogen atom or a halogen atom). } means. ] There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. that are characterized by reacting the compound represented by with phthaloyl dichloride in the presence of a Lewis acid ▼ [In the formula, R^1 and R^2 are as above. have the same meaning. ] A method for producing a tetrahydronaphthacene derivative represented by