RU2554937C1 - METHOD OF OBTAINING ANTHRA[2,3-b]FURAN-3-CARBOXYLIC ACID - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to chemistry of heterocyclic compounds, namely to novel method of obtaining 4,11-dihydroxy-5,10-dioxo-2-methylanthra[2,3-b]furan-3-carboxylic acid of formula

which can be used as half-product for obtaining biologically active substances and dyes. Method consists in successive carrying out stage of haterocyclisation of 2,3-dihalogen-derivative of 1,4-dihydroxyanthraquinone with tertiary ether of acetoacetic acid in presence of base with heating in inert solvent and further stage of acidic hydrolysis of formed tertiary ether of 4,11-dihydroxy-5,10-dioxo-2-methylanthra[2,3-b]furan-3-carboxylic acid.

EFFECT: increase of target product output.

9 cl, 6 ex

Description

Technical field

The invention relates to the chemistry of heterocyclic compounds, and in particular to a method for producing 4,11-dihydroxy-5,10-dioxo-2-methylantra [2,3-b] furan-3-carboxylic acid, which can be used for the synthesis of biologically active substances or dyes.

State of the art

Derivatives of 4,11-dihydroxy-5,10-dioxo-2-methylanthra [2,3-b] furan-3-carboxylic acid can be used in various fields of science and technology, for example, for dyeing fabrics [patent SU 973577 (1983) ], as fluorescent dyes or labels [Schekotikhin A.E. et al. ZhORKh, 2007, 43 (11), 1687], photochromic materials [Schekotikhin A.E et al. ZhORKh, 2008, 44 (6), 864] or medicines [RF patent No. 2412166 (2011)]. The only known method for producing 4,11-dihydroxy-5,10-dioxo-2-methylanthra [2,3-b] furan-3-carboxylic acid is described by M.V. Gorelik [Gorelik M.V., Mishina E.V. ZhORKh, 1983, 2185]. In this scheme, 1,4-dihydroxy-2,3-dichlorantrachinone (2,3-dichloroquinisarin 1a) was used as the starting material for heterocyclization, the condensation of which with ethyl acetoacetic acid (2a) gives 4,11-dihydroxy- ethyl ester 5,10-dioxo-2-methylanthra [2,3-b] furan-3-carboxylic acid (3a) in 58% yield (Scheme A). Ether 3a turned out to be quite resistant to the action of alkalis and acids; therefore, its hydrolysis to the target 4,11-dihydroxy-5,10-dioxo-2-methylantra [2,3-b] furan-3-carboxylic acid (4) is carried out in hard conditions by prolonged heating in sulfuric acid at 100 ° C.

The previously known scheme has a number of significant drawbacks that reduce its effectiveness for the preparative synthesis of anthra [2,3-b] furan-3-carboxylic acid 4. First of all, we were not able to reproduce the yield of intermediate ethyl ester 3a described in the literature (58%). The maximum yield of ether 3a, obtained by us according to the method described in the patent [SU 973577 (1983)], is 38-42%. Thus, carboxylic acid 4 was obtained according to scheme A with a total yield of less than 30%. Other disadvantages of this preparation method include the difficulties of isolation and purification of ester 3a associated with its low solubility, as well as the formation of a side derivative of angular anthrafurandione at the heterocyclization stage [SU 973577 (1983), Gorelik MV, Mishina EV. ZhORKh, 1983, 2185] and a strong grinding of the reaction mass during cyclization. In addition, the disadvantages of the described method for the synthesis of acid 4 are the stringent conditions for the stage of hydrolysis of ethyl ether 3a, which requires prolonged heating in sulfuric acid at 100 ° C and a high consumption of sulfuric acid itself (40 ml per 1 g of acid 4). This method requires thorough washing of the precipitated product with a large volume of water. One of the critical factors important for the practical use of 4,11-dihydroxy-5,10-dioxo-2-methylanthra [2,3-b] furan-3-carboxylic acid (4) upon receipt of medicinal substances or fluorescent materials on its basis , there may be a purity of the target acid 4. The product obtained by this method has a purity of 90-95%, therefore, it requires additional purification by crystallization from acetic acid.

These disadvantages reduce the effectiveness of the previously described method for the preparative preparation of 4,11-dihydroxy-5,10-dioxo-2-methylanthra [2,3-b] furan-3-carboxylic acid (4). Therefore, the purpose of this invention was to eliminate the disadvantages associated with the low yield of the product, as well as the difficulties of synthesis, isolation and purification inherent in the previously known method for producing 4,11-dihydroxy-5,10-dioxo-2-methylanthra [2,3-b ] furan-3-carboxylic acid (4).

Disclosure of invention

In our claimed improved two-stage method for producing 4,11-dihydroxy-5,10-dioxo-2-methylanthra [2,3-b] furan-3-carboxylic acid (4) in the first stage (Scheme B) for heterocyclization, there can be The 2,3-dichloro- or 2,3-dibromo derivatives of quinisarin (1a or 1b) and the acetoacetic acid ester 2b were used. An important feature of the claimed synthesis method is the use for the cyclization of anthrafurandione tertiary esters of acetoacetic acid 2b, where R is a tertiary hydrocarbon radical.

As the base (B) for heterocyclization, various organic or inorganic bases widely used in organic synthesis can be used, for example (without limitation to the listed): K ₂ CO ₃ , Cs ₂ CO ₃ , Na ₂ CO ₃ , K ₃ PO ₄ , triethylamine, ethyldiisopropylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,4-diazabicyclo [2.2.2] octane and the like. The interaction of these reagents is carried out in an inert solvent at a temperature of from about 100 ° C to 140 ° C and a molar ratio of reagents (1) / (2b) / (B) from about 1: 1: 2 to 1:10:10.

In the most preferred embodiment of the invention, in the first step (Scheme B), 4,11-dihydroxy-5,10-dioxo-2-methylanthra [2,3-b] furan-5,10-dion-3-carboxylic tert-butyl ether is obtained acids (3b). The starting materials for its synthesis are 2,3-dibromo-1,4-dihydroxyanthraquinone (2,3-dibromoquinizarin 1b) and acetoacetic acid tert-butyl ester (2b, R = t-Bu), and cyclization is carried out by potassium carbonate in an inert solvent at a temperature of from about 120 ° C to 130 ° C and a molar ratio of reactants (1) / (2b) / (B) of about 1: 3: 3.

In the second stage of the proposed method (Scheme B), the acid hydrolysis of tertiary ester 3b is carried out, leading to the target 4,11-dihydroxy-5,10-dioxo-2-methylantra [2,3-b] furan-3-carboxylic acid (4) .

The cleavage of ester 3b (Scheme B) can be carried out at a temperature of from about 20 ° C to 110 ° C. However, in preferred embodiments, the hydrolysis is carried out at a temperature of from about 20 ° C to 40 ° C. Various organic or inorganic acids in or without an inert solvent can be used to decompose tertiary ester 3b, for example trifluoroacetic acid, formic acid, methanesulfonic acid, n-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and the like. To simplify the isolation of the final product and to achieve its high purity, in the most preferred embodiments of the invention, volatile acids, for example trifluoroacetic, formic or hydrochloric, are used at this stage of the synthesis.

Thus, the task is solved by the following details of the invention. A key feature of the present invention is the use of acetoacetic acid tertiary esters in the heterocyclization step, leading to the formation of 4,11-dihydroxy-5,10-dioxo-2-methylanthra [2,3-b] furan-3-carboxylic acid tertiary esters 3b. Replacing ethyl acetoacetic acid 2a with tertiary acetoacetic acid, for example tert-butyl 2b (R = t-Bu), increases the yield of target compound 4. In addition, the presence of a more lipophilic tertiary ester residue in intermediate 3b facilitates its isolation and purification due to better solubility compared to ethyl analog 3a.

An important factor leading to an increase in the yield of the product of heterocyclization of anthrafurandione 3b is the method of adding a base. As a result of extensive experimental studies, we found that the addition of a base to a reaction mixture preheated to approximately 120 ° C leads to a noticeable increase in the yield of product 3b and an increase in its quality due to a decrease in the resinification of the reaction mass and a decrease in the formation of a side angular heterocyclization product. This, apparently, is explained by the fact that during heterocyclization of anthrafurandione 3a according to the previously described technique [SU 973577 (1983), Gorelik MV, Mishina EV ZhORKh, 1983, 2185], which consists in heating all reagents in an inert solvent to 120 ° C and then keeping the mixture at this temperature, while heating the reaction mass from 20 to 120 ° C, the hydroxy groups of the quinizarin derivative 1a are ionized under the action of an excess of base, which reduces the reactivity of halogen atoms and leads to specific angular cyclization of the furan nucleus. Obviously, with the gradual addition of the base to the reaction mixture heated to 120 ° С, the heterocyclization of linear anthrafurandione 3b occurs earlier than the hydroxy groups of the substrate 1b are ionized, which leads to a decrease in the proportion of the by-product angular product and a decrease in the resinification of the reaction mass.

The combination of all these factors allows to reduce the consumption of solvents and to simplify the procedure for cleaning intermediate 3b. Thus, technical ether 3b obtained by this method can be purified by filtering the solution through a small layer of silica gel, while column chromatography must be used to purify its ethyl analog 3a obtained according to Scheme A.

The decomposition of tertiary esters of carboxylic acids under conditions of acid hydrolysis proceeds much faster than ethyl esters, due to which milder conditions (room temperature) and milder organic and inorganic acids can be used for hydrolysis of ester 3b. Hydrolysis of tertiary ester 3b allows to obtain 4,11-dihydroxy-5,10-dioxo-2-methylanthra [2,3-b] furan-3-carboxylic acid (4) of high purity without additional purification with a yield close to quantitative.

In addition, according to another aspect of the present invention, in the preferred embodiment of the heterocyclization, the more reactive dibromoquinizarin 1b is used [Kim S.H. et. al. Dyes and Pigments, 1986, 7, 93], the use of which allows to reduce the reaction time, as well as increase the yield of 4,11-dihydroxy-5,10-dioxo-2-methylanthra [2,3-b] furan-3-carbonic ester acids 3b. At the heterocyclization stage, both inorganic and organic bases can be used, resulting in close yields of the desired products. Given the highest yield of anthrafurandiones of formula 4, as well as the availability in a preferred embodiment of the claimed invention, the use of anhydrous potassium carbonate is most preferred as a base in the cyclization step (Scheme B).

The term "tertiary radical" in the present invention means a methyl group, thrice independently substituted by alkyl or aryl substituents, each of which has independently from 1 to 6 carbon atoms. Examples of tertiary radicals are primarily (without limitation) tert-butyl, tert-pentyl, 1,1,1- (triethyl) methyl, 1,1,1- (triisoamyl) methyl, triphenylmethyl, preferably tert-butyl.

The reactions described in the application description are preferably carried out at atmospheric pressure at a temperature of from about 0 ° C to 180 ° C, more preferably from 20 ° C to 140 ° C.

"Inert organic solvent" means a solvent inert under the conditions described in the text of the reactions, including, for example, dimethyl sulfoxide, Ν, N-dimethylformamide (DMF), Ν, N-dimethylacetamide (DMAA), N-methylpyrrolidone, sulfolane, benzene, toluene , acetonitrile, tetrahydrofuran, tetrachloromethane, chloroform, dichloromethane, dichloroethane, ethyl acetate, acetone, methyl ethyl ketone, dioxane, pyridine, acetic acid and the like. Preferably, the cyclization step of anthrafurandione 3b should be carried out in polar aprotic solvents, for example in dimethyl sulfoxide, Ν, N-dimethylformamide, Ν, N-dimethylacetamide, N-methylpyrrolidone, sulfolane, more preferably in dimethyl sulfoxide. Preferably, chloroform, dichloromethane, dichloroethane, carbon tetrachloride, benzene, toluene, dioxane, tetrahydrofuran, acetic acid are used in the ester 3b cleavage step, or hydrolysis is carried out in the absence of solvent in an excess of acid.

Thus, the new synthesis method of 4,11-dihydroxy-5,10-dioxo-2-methylanthra [2,3-b] furan-3-carboxylic acid (4), which is the subject of the present invention, has several important advantages compared to previously known method:

1. A large total yield (about 60-67%) of the target 4,11-dihydroxy-5,10-dioxo-2-methylantra [2,3-b] furan-3-carboxylic acid (4) and its high purity.

2. A simplified procedure for the isolation and purification of intermediate 3b and the final 4,11-dihydroxy-5,10-dioxo-2-methylantra [2,3-b] furan-3-carboxylic acid (4).

3. Greater synthesis efficiency by reducing the reaction time, temperature of the hydrolysis stage, as well as reducing the consumption of reagents, solvents and sorbents at the stages of synthesis and purification of products.

The starting materials and reagents used in the preparation of anthra [2,3-b] furan-3-carboxylic acid 4 are commercially available chemicals supplied by companies such as Aldrich Chemical Co., Acros and others, or they can be obtained by methods , well-known specialist in this field, according to the techniques described in the literature.

The structure of the target 4,11-dihydroxy-5,10-dioxo-2-methylantra [2,3-b] furan-3-carboxylic acid (4) and its intermediate (3b) was confirmed by NMR spectroscopy, EPS, and mass high resolution spectra. The purity of the products was confirmed by HPLC analysis.

The following non-limiting examples are given to illustrate details of an embodiment of the present invention. Specialists in the field of organic chemistry will easily understand that in the implementation of the present invention can be used various similar options for the synthesis of the target anthra [2,3-b] furan-3-carboxylic acid.

Example 1

A mixture of 6.4 g (16 mmol) of 2,3-dibromoquinizarin (1b) and 9.0 ml (54 mmol) of acetoacetic acid tert-butyl ester (2b, R = t-Bu) in DMSO (120 ml) is heated to 120 ° C, after whereupon at this temperature, 7.0 g (50 mmol) of crushed anhydrous K ₂ CO _{3 are} carefully added to the stirred mixture. After making the base, the mixture is heated to 125 ° C and maintained with stirring for 15 minutes at this temperature. The reaction mass is cooled and, with stirring, carefully poured into a mixture of water (400 ml) and conc. hydrochloric acid (9.0 ml). The precipitate formed is filtered off, washed with water (2 × 200 ml), ethanol (30 ml) and dried. The precipitate was dissolved in boiling chlorobenzene (200 ml) and the hot solution was filtered through a porous filter with a layer of silica gel (30 g). The silica gel filter was washed with a hot mixture of toluene - chlorobenzene - ethyl acetate (3 × 150 ml, 3: 1: 1). The combined filtrate was evaporated in vacuo and the residue was crystallized from chlorobenzene (60 ml). The precipitated crystals are filtered off, washed with a mixture of n-hexane - diethyl ether (2 × 50 ml, 5: 1) and dried in air. The yield of orange crystals of tert-butyl ether 3b is 4.42 g (70%). Mp = 236-238 ° C.

TLC: Rf = 0.45, toluene-ethyl acetate (20: 1). HPLC (Kromasil 100-5 C18, 4.6 × 250 mm column (Akzo Nobel); eluents: A - H ₃ PO ₄ (0.01 m), B - MeCN; gradient B 70 → 95% (20 min); LW = 260 nm ): t _R = 24.6 min, purity 98%. ESP, λ _max , nm, (logε): 260 (4.4), 479 (4.0), 509 (3.9). ¹ H NMR spectrum (400 MHz, DMSO-d ₆ ), δ, ppm: 14.53 (1H, s, OH); 13.87 (1H, s, OH); 8.37 (2H, m, H-6.9); 7.81 (2H, m, H-7.8); 2.75 (3H, s, CH ₃ ); 1.65 (9H, s, OBu ^t ). Found: m / z (ESI), 395.1133 [M + H] ⁺ . C ₂₂ H ₁₉ O ₇ . Calculated: 395.1125.

Example 2

A mixture of 3.2 g (8 mmol) of 2,3-dibromoquinizarin (1b) and 4.5 ml (27 mmol) of acetoacetic acid tert-butyl ester (2b, R = t-Bu) and 3.5 g (25 mmol) of anhydrous powdered K ₂ CO ₃ in DMSO (60 ml) is heated to 125 ° C and maintained with stirring for 20 min at this temperature. The reaction mass is cooled and the product is isolated according to the procedure described in example 1. The yield of orange crystals of tert-butyl ether 3b is 1.7 g (53%). Mp and the spectral characteristics of the obtained product are identical to those described in example 1.

Example 3

A mixture of 3.2 g (8 mmol) of 2,3-dibromoquinizarin (1b) and 4.5 ml (27 mmol) of acetoacetic acid tert-butyl ester (2b, R = t-Bu) in DMSO (120 ml) is heated to 60 ° C, after whereupon, at this temperature, 8.3 g (25 mmol) of anhydrous powdered Cs ₂ CO _{3 are} carefully added to the stirred mixture. After making the base, the mixture is heated to 125 ° C and maintained with stirring for 15 minutes at this temperature. The reaction mass is cooled and the product is isolated according to the procedure described in example 1. The yield of orange crystals of tert-butyl ether 3b is 1.9 g (60%). Mp and the spectral characteristics of the obtained product are identical to those described in example 1.

Example 4

A mixture of 2.5 g (8 mmol) of 2,3-dichloroquinizarin (1a) and 4.5 ml (27 mmol) of acetoacetic acid tert-butyl ester (2b, R = t-Bu) in DMSO (120 ml) is heated to 60 ° C, after which at this temperature 3.5 g (25 mmol) of crushed anhydrous K ₂ CO _{3 are} carefully added to the stirred mixture. After making the base, the mixture is heated to 125 ° C and kept under stirring for 20 minutes at this temperature. The reaction mass is cooled and the product is isolated according to the procedure described in example 1. The yield of orange crystals of tert-butyl ether 3b is 1.8 g (57%). Mp and the spectral characteristics of the obtained product are identical to those described in example 1.

Пример 5

Example 5

Trifluoroacetic acid (15 ml) was added to a stirred suspension of 4.0 g (10 mmol) of tert-butyl ether 3b in chloroform (50 ml). The mixture is stirred for 1.5-2 hours at room temperature until the reaction is complete and the volatile components of the mixture are distilled off in vacuo. Dichloromethane (30 ml) was added to the resulting residue, the mixture was boiled with stirring for 5 minutes, cooled and the resulting precipitate was filtered off. The product was washed with n-hexane and dried in air. The yield of the target anthrafuran-3-carboxylic acid 4 is 3.3 g (96%), in the form of brilliant red crystals with a melting point> 280 ° C (mp. 299-301 ° C [Gorelik MV, Mishina E .V. ZhORKh, 1983, 2185]).

TLC: Rf = 0, chloroform-methanol (3: 1). HPLC (Kromasil 100-5 C18, 4.6 × 250 mm column (Akzo Nobel); eluents: A — H ₃ PO ₄ (0.01 m), B — MeCN; gradient B 70 → 95% (20 min); LW = 260 nm ): t _R = 8.2 min, purity 99%. ESP, λ _max , nm, (logε): 259 (4.4), 481 (4.0). ¹ H NMR spectrum (400 MHz, DMSO-d ₆ ), δ, ppm: 8.19 (2H, m, H-6.9); 7.91 (2H, m, H-7.8); 2.69 (3H, s, CH ₃ ). Found: m / z (ESI), 339.0504 [M + H] ⁺ . C ₁₈ H ₁₁ O ₇ . Calculated: 339.0499.

Example 6

A mixture of 2.0 g (10 mmol) of tert-butyl ether 3b and formic acid (15 ml) was stirred at room temperature until the reaction was completed and evaporated in vacuo. Dichloromethane (15 ml) was added to the resulting residue, the mixture was boiled with stirring for 5 minutes, cooled and the resulting precipitate was filtered off. The product was washed with n-hexane and dried in air. The yield of the desired anthrafuran-3-carboxylic acid 4 is 1.6 g (94%), in the form of brilliant red crystals. Mp and the spectral characteristics of the obtained product are identical to those described in example 5.

Claims (9)

1. The method of obtaining 4,11-dihydroxy-5,10-dioxo-2-methylanthra [2,3-b] furan-3-carboxylic acid of formula I

consisting in sequentially carrying out the heterocyclization step of a 2,3-dihalo derivative of 1,4-dihydroxyanthraquinone with an acetic acid tertiary ester in the presence of a base when heated in an inert solvent and the subsequent acid hydrolysis of the resulting 4,11-dihydroxy-5,10-dioxo-2 tertiary ester methyl [2,3-b] furan-3-carboxylic acid. 2. The method of producing compound I according to claim 1, wherein in the heterocyclization step, tert-butyl acetoacetic acid ester is used as the acetoacetic acid tertiary ester, and the 4,11-dihydroxy-5,10-dioxo-tert-butyl ester is an intermediate 2-methylanthra [2,3-b] furan-3-carboxylic acid. 3. The method of producing compound I according to claim 1 or 2, in which 2,3-dibromo-1,4-dihydroxyanthraquinone is used for heterocyclization. 4. The method of obtaining compound I according to claim 1 or 2, in which the base at the stage of heterocyclization is added to the remaining components of the reaction mixture at a temperature of from 110 to 130 ° C. 5. The method of producing compound I according to claim 1 or 2, in which the heterocyclization step is carried out by keeping the reaction mixture at a temperature of from 110 ° C to 130 ° C. 6. The method of producing compound I according to claim 1 or 2, in which, at the stage of condensation, potassium carbonate is used as a base. 7. The method for producing compound I according to claim 1 or 2 with a molar ratio of reactants in the heterocyclization step of approximately 1: 3: 3 (2,3-dihalo-1,4-dihydroxyanthraquinone / acetoacetate / base). 8. The method of producing compound I according to claim 1 or 2, in which dimethyl sulfoxide is used as an inert solvent to carry out the condensation step. 9. A method for producing compound I according to claim 1 or 2, wherein the step of hydrolyzing the 4,11-dihydroxy-5,10-dioxo-2-methylanthra [2,3-b] furan-3-carboxylic acid intermediate tertiary ester is carried out at the action of trifluoroacetic, formic or hydrochloric acids.