3-Arylcoumarin intermediates and their preparation methods

Abstract

This invention discloses a method for preparing 3-aranylcoumarin intermediate compounds, including step (1) in an inert gas environment, compound 1 reacts with compound 2 Michaelis acid and compound 3 trifluoroacetic anhydride in the first reaction solvent under the action of a metal catalyst at a reaction temperature of 0-50℃. After the reaction is complete, compound 4 is obtained. Compared with the prior art, the key raw materials in the synthetic route used in this invention are cheap and readily available; the reaction conditions are mild, the operation is convenient, the process safety is high, and it is friendly to operators; the reaction yield is high, the product purity is high, which greatly reduces the production cost and can fully meet the needs of production of products at the ton level or above.

Description

Technical Field

[0001] This invention relates to the field of fluorescent dye synthesis technology, specifically to 3-aranylcoumarin intermediate compounds and their preparation methods. Background Technology

[0002] Fluorescent dyes can stain proteins, nucleic acids, glycans, and other structures, and can even detect inanimate substances such as calcium ions. By utilizing the specific binding of fluorescent substances to corresponding antibodies or antigens, the analytes can be analyzed locally, qualitatively, and quantitatively. This method is highly specific, sensitive, and intuitive, and is an immunolabeling technique.

[0003] Coumarins are a class of fluorescent dyes with a benzopyranone structure, representing the parent nucleus of a large class of coumarin compounds found in the plant kingdom. Coumarins typically exhibit blue fluorescence under ultraviolet light (emission range ~410 to 470 nm) and are frequently used as blue dyes in multicolor fluorescent target experiments. Introducing an electron-donating group (such as an amino group) at the 7-position enhances fluorescence; introducing an electron-withdrawing group (such as a carboxylic acid group) at the 3- or 4-position also enhances fluorescence. Coumarins themselves have relatively weak fluorescence; introducing these groups increases the probability of intramolecular charge transfer, thus enhancing fluorescence, making it observable even under visible light. Furthermore, introducing functional groups at the 3- or 4-position can control the excitation and emission wavelengths of coumarin fluorescence, thus adjusting the fluorescence color; for example, Coumarin 6 and Coumarin 545 can emit green fluorescence. Coumarin has advantages such as high fluorescence quantum yield, tunable photophysical and photochemical properties, good photostability, good biocompatibility, simple synthesis and easy structural modification.

[0004] Carbonyl groups are also a common type of reactive group in organic chemistry. They possess good reactivity and can thus be used as starting groups to transform into various other groups. Therefore, how to introduce carbonyl groups, especially aryl carbonyl groups (i.e., aryl ketones), into the coumarin structure is a current research direction. However, to date, there are very few reports on this topic.

[0005] 3-Arylcoumarin derivatives, as an important category of coumarin derivatives containing a carbonyl group at the 3-position, have received attention in recent years for their chemical synthesis and biological activity research. Currently, the synthesis of 3-aroylcoumarin derivatives typically involves the reaction of coumarin with benzoyl chloride under amino zinc and amino magnesium base conditions (Wunderlich SH, Rohbogner CJ, Unsinn A, et al. Scaleable preparation of functionalized organometallics via directed ortho metalation using Mg- and Zn-amide bases[J]. Org. Process Res Dev, 2010, 14(2): 339-345.), or the refluxing of o-hydroxybenzaldehyde with α-aryl ketene dithioacetals (AKDTAs) in THF under a catalytic amount of piperidine (Prakash Rao HS, Sivakumar S. Condensation of α-aroylketene dithioacetals and 2-hydroxyaryl akdehydes results in facile synthesis of a combinatorial library of 3-aroylcoumarins[J]. J Org. Chem, 2006, 71(23): 8715-8723.), but these methods require relatively harsh conditions and complex raw materials, lacking economy and practicality. The literature "Wang H, Zhou SL, Guo LN, et al. Diacylation of coumarins by silver-catalyzed decarboxylative cross-coupling[J].Tetrahedron, 2015, 71(4): 630-636." uses AgNO3 as catalyst and K2S2O8 as oxidant to react coumarins with carbonyl acids to obtain 3-ararylcoumarin derivatives and 3,4-diararylcoumarin derivatives.The literature “Yan KL, Yang DS, Wei W, et al. Silver-mediated radical cyclization of alkynoates and α-keto acids leading to coumarins via cascade double CC bond formation[J]. J Org Chem, 2015, 80(3): 1550-1556” uses Ag2CO3 as a catalyst, K2S2O8 as an oxidant, and alkyne esters as raw materials to react with carbonyl acids via free radical reactions to obtain 3-arcaryococoumarin derivatives. However, these synthetic methods use expensive carbonyl acids as raw materials or use unavailable reaction precursors. Therefore, there is an urgent need to explore a simple, mild, and high-yield synthetic method for 3-arcaryococoumarin derivatives. Summary of the Invention

[0006] In view of the problems existing in the prior art, the present invention develops a 3-aranoylcoumarin intermediate compound and its preparation method, as well as the preparation of 3-aranoylcoumarin compounds using the intermediate compound. The preparation method has the advantages of readily available raw materials, low cost, easy industrial-scale production, high yield and high purity.

[0007] One of the technical problems to be solved by the present invention is to provide a method for preparing a 3-aranylcoumarin intermediate compound, comprising the step (1) reacting compound 1 with compound 2 Michaelis acid and compound 3 trifluoroacetic anhydride in an inert gas environment in a first reaction solvent under the action of a metal catalyst at a reaction temperature of 0-50°C, and after the reaction is complete, compound 4 is obtained, and its reaction formula is shown below: In the formula, R1, R2, R3 and R4 are independently selected from hydrogen, methyl, ethyl, C3-C8 alkyl, phenyl, diethylamino, dimethylamino, methoxy or ethoxy.

[0008] In a preferred embodiment of the present invention, the first reaction solvent is one or more of the following: dichloroethane, ethyl acetate, dichloromethane, acetonitrile, methyl acetate, acetone, butanone, isopropyl acetate, butyl acetate, ethylene glycol diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, chlorobenzene, nitrobenzene, or o-dichlorobenzene.

[0009] In a preferred embodiment of the present invention, the aforementioned first metal catalyst is one or more of sodium trifluoroacetate, potassium trifluoroacetate, lithium trifluoroacetate, cesium trifluoroacetate, or magnesium trifluoroacetate.

[0010] In a preferred embodiment of the present invention, the molar ratio of the first compound 1, the second compound 2 (Missell's acid), and the third compound 3 (trifluoroacetic anhydride) is 1:1-5:1-10.

[0011] In a preferred embodiment of the present invention, the molar ratio of the first metal catalyst to compound 1 is 0.0001 to 0.2:1.

[0012] The second technical problem to be solved by this invention is to provide a method for preparing 3-arcaryoylcoumarin intermediates, the structural formula of which is shown in compound 4. In the formula, R1, R2, R3 and R4 are independently selected from hydrogen, methyl, ethyl, C3-C8 alkyl, phenyl, diethylamino, dimethylamino, methoxy or ethoxy.

[0013] The third technical problem to be solved by this invention is to provide a method for preparing 3-aranylcoumarin compounds from the above-mentioned 3-aranylcoumarin intermediate compounds, which further includes step (2) reacting compound 4 and compound 5 in a second reaction solvent under the action of a catalyst at a reaction temperature of -20 to 200°C, and after the reaction is complete, compound 6, a 3-aranylcoumarin compound, is obtained, and its reaction formula is as follows: In the formula, R1, R2, R3 and R4 are independently selected from hydrogen, methyl, ethyl, C3-C8 alkyl, phenyl, diethylamino, dimethylamino, methoxy or ethoxy, and Ar is selected from 2-thienyl, phenyl, 2-furanyl, 2-naphthyl, 4-methoxyphenyl, 4-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-dimethylaminophenyl.

[0014] In a preferred embodiment of the present invention, the second reaction solvent described above is one or more of dichloroethane, ethyl acetate, dichloromethane, acetonitrile, methyl acetate, acetone, butanone, isopropyl acetate, butyl acetate, ethylene glycol diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, or dioxane.

[0015] In a preferred embodiment of the present invention, the catalyst is one or more of methanesulfonic acid, trifluoromethanesulfonic acid, p-nitrobenzenesulfonic acid, o-nitrobenzenesulfonic acid, benzenesulfonic acid, or p-methylbenzenesulfonic acid.

[0016] In a preferred embodiment of the present invention, the molar ratio of the first catalyst to compound 4 is 0.0001 to 0.2:1. Beneficial effects

[0017] Compared with existing technologies, the key raw materials in the synthetic route used in this invention are inexpensive and readily available; the reaction conditions are relatively mild, the operation is convenient, the process is highly safe, and it is operator-friendly; the reaction selectivity is high, the reaction yield is high, and the product purity is high, which greatly reduces production costs and can fully meet the needs of production at the ton level or above. Detailed Implementation

[0018] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0019] Unless otherwise specified, all materials and reagents used in the following examples are commercially available. Example 1

[0020]

[0021] Step S1: Preparation of 7-diethylaminocoumarin-3-carboxylic acid trifluoroacetic anhydride Maintaining a slight positive nitrogen pressure, add 2 L of dichloroethane, 193.24 g (1.0 mol) of 4-(diethylamino)salicylaldehyde, 158.54 g (1.1 mol) of Michaelis-Menten acid, 231.03 g (1.1 mol) of trifluoroacetic anhydride, and 13.61 g (0.1 mol) of sodium trifluoroacetate sequentially to a 5 L reaction flask. After the addition is complete, stir well and heat the reaction solution to 40 °C. Maintain the reaction temperature for 24 hours until completion.

[0022] The reaction solution was cooled to room temperature, and 63.59 g (0.6 mol) of solid sodium carbonate was added. The mixture was stirred vigorously for 1 hour. The solution was filtered to remove the solid, and the filtrate was collected. 2 L of petroleum ether was added to the filtrate, and the mixture was cooled to 0°C and kept at this temperature overnight. A large amount of solid precipitated. The solid was filtered, and the filter cake was collected to obtain 329.78 g (0.923 mol) of a yellow solid product. Yield: 92.3%; Product purity: 98.13% (HPLC); NMR data: 1 H NMR (400MHz, CDCl3): δ 8.11 (s, 1H), 7.31 (d, 1H), 6.59 (d, 1H), 6.47 (d, 1H), 3.46 (q, 4H), 1.23 (t, 6H).

[0023] Step S2: Preparation of 7-diethylamino-3-thiophenecarboxylocoumarin Add 1 L of dichloroethane, 329.78 g (0.923 mol) of 7-diethylaminocoumarin-3-carboxylic acid trifluoroacetic anhydride, and 79.51 g (0.945 mol) of thiophene sequentially to a 2 L reaction flask. After the addition is complete, stir well. Then add 8.65 g (0.09 mol) of methanesulfonic acid and stir well. The reaction solution is then heated to 70°C and stirred for 6 hours until the reaction is complete.

[0024] The reaction solution was allowed to cool naturally to room temperature, and 200 mL of saturated sodium bicarbonate solution was added to bring the solution to alkalinity. The mixture was separated, and the organic phase was collected. The organic phase was cooled to 0°C and kept at this temperature for 8 hours to allow crystallization. A large amount of solid continued to precipitate. The solid was filtered, and the filter cake was collected to obtain 292.69 g (0.894 mol) of yellow solid product.

[0025] Yield: 96.9%, overall yield of the two-step reaction: 89.4%, product purity: 99.15% (HPLC); NMR data: 1 H NMR (400MHz, CDCl3): δ 8.01 (s, 1H), 7.71-7.68 (m, 1H), 7.63-7.60 (m, 1H), 7.30 (d, 1H), 7.08-7.04 (m, 1H), 6.59 (d, 1H), 6.46 (d, 1H), 3.45 (q, 4H), 1.23 (t, 6H). Example 2

[0026]

[0027] Step S1: Preparation of 7-dimethylaminocoumarin-3-carboxylic acid trifluoroacetic anhydride Maintaining a slight positive nitrogen pressure, add 2 L of ethyl acetate, 193.24 g (1.0 mol) of 4-(dimethylamino)salicylaldehyde, 288.26 g (2.0 mol) of Michaelis-Menten acid, 525.08 g (2.5 mol) of trifluoroacetic anhydride, and 1.52 g (0.01 mol) of potassium trifluoroacetate sequentially to a 5 L reaction flask. After the addition is complete, stir well and heat the reaction solution to 30 °C. Maintain the reaction temperature for 16 hours until completion.

[0028] The reaction solution was cooled to room temperature, and 63.59 g (0.6 mol) of solid sodium carbonate was added. The mixture was stirred vigorously for 1 hour. The solution was filtered to remove the solid, and the filtrate was collected. 2 L of petroleum ether was added to the filtrate, and the mixture was cooled to 0°C and kept at this temperature overnight. A large amount of solid precipitated. The solid was filtered, and the filter cake was collected to give 307.83 g (0.935 mol) of a yellow solid product. Yield: 93.5%; Product purity: 98.27% (HPLC); NMR data: 1H NMR (400MHz, CDCl3): δ 8.11 (s, 1H), 7.31 (d, 1H), 6.59 (d, 1H), 6.47 (d, 1H), 3.03 (s, 6H).

[0029] Step S2: Preparation of 7-dimethylamino-3-benzoylcoumarin Add 1 L of 2-methyltetrahydrofuran, 307.83 g (0.935 mol) of 7-dimethylaminocoumarin-3-carboxylic acid trifluoroacetic anhydride, and 365.16 g (4.675 mol) of benzene sequentially to a 2 L reaction flask, and stir well. Then add 7.91 g (0.05 mol) of benzenesulfonic acid and stir well. The reaction solution is then heated to 75°C and stirred for 4 hours until the reaction is complete.

[0030] The reaction solution was allowed to cool naturally to room temperature, and 200 mL of saturated sodium bicarbonate solution was added to bring the solution to alkalinity. The mixture was separated, and the organic phase was collected. The organic phase was cooled to 0°C and kept at this temperature for 8 hours to allow crystallization. A large amount of solid continued to precipitate. The solid was filtered, and the filter cake was collected to obtain 252.84 g (0.862 mol) of yellow solid product.

[0031] Yield: 92.2%, overall yield of the two-step reaction: 86.2%, product purity: 99.21% (HPLC); NMR data: 1 H NMR (400MHz, CDCl3): δ 8.01 (s, 1H), 7.78-7.74 (m, 2H), 7.60-7.51 (m, 3H), 7.31 (d, 1H), 6.59 (d, 1H), 6.47 (d, 1H), 3.03 (s, 6H). Example 3

[0032]

[0033] Step S1: Preparation of 4-methylcoumarin-3-carboxylic acid trifluoroacetic anhydride Maintaining a slight positive nitrogen pressure, add 2 L of butanone, 136.15 g (1.0 mol) of 6-methylsalicylaldehyde, 720.65 g (5.0 mol) of Michaelis-Menten acid, 1050.15 g (5.0 mol) of trifluoroacetic anhydride, and 1.20 g (0.01 mol) of lithium trifluoroacetate sequentially to a 5 L reaction flask. After the addition is complete, stir well and heat the reaction solution to 50 °C. Maintain the reaction temperature for 48 hours until completion.

[0034] The reaction solution was cooled to room temperature, and 63.59 g (0.6 mol) of solid sodium carbonate was added. The mixture was stirred vigorously for 1 hour. The solution was filtered to remove the solid, and the filtrate was collected. 2 L of petroleum ether was added to the filtrate, and the mixture was cooled to 0°C and kept at this temperature overnight. A large amount of solid precipitated. The solid was filtered, and the filter cake was collected to obtain 282.78 g (0.942 mol) of a yellow solid product. Yield: 94.2%; Product purity: 98.55% (HPLC); NMR data: 1 H NMR (400MHz, CDCl3): δ 8.11 (s, 1H), 7.51 (t, 1H), 7.28 (d, 1H), 7.09 (d, 1H), 2.45 (s, 3H).

[0035] Step S2: Preparation of 4-methyl-3-p-dimethylaminobenzoylcoumarin Add 1 L of ethylene glycol diethyl ether, 282.78 g (0.942 mol) of 4-methylcoumarin-3-carboxylic acid trifluoroacetic anhydride, and 118.15 g (0.975 mol) of N,N-dimethylaniline sequentially to a 2 L reaction flask, and stir well. Then add 13.51 g (0.09 mol) of trifluoromethanesulfonic acid and stir well. The reaction solution is then heated to 120 °C and stirred for 6 hours until the reaction is complete.

[0036] The reaction solution was allowed to cool naturally to room temperature, and 200 mL of saturated sodium bicarbonate solution was added to bring the solution to alkalinity. The mixture was separated, and the organic phase was collected. The organic phase was cooled to 0°C and kept at this temperature for 8 hours to allow crystallization. A large amount of solid continued to precipitate. The solid was filtered, and the filter cake was collected to obtain 277.54 g (0.903 mol) of yellow solid product.

[0037] Yield: 95.8%, overall yield of the two-step reaction: 90.3%, product purity: 99.26% (HPLC); NMR data: 1 H NMR (400MHz, CDCl3): δ 8.11 (s, 1H), 7.79 (d, 2H), 7.51 (t, 1H), 7.28 (d, 1H), 7.09 (d, 1H), 6.63 (d, 1H), 3.07 (s, 6H), 2.45 (s, 3H).

[0038] Comparative Example 1

[0039]

[0040] Step S1: Preparation of 7-diethylaminocoumarin-3-carboxylic acid trifluoroacetic anhydride Maintaining a slight positive pressure of nitrogen, add 2 L of dichloroethane, 193.24 g (1.0 mol) of 4-(diethylamino)salicylaldehyde, 158.54 g (1.1 mol) of Michaelis-Menten acid, 231.03 g (1.1 mol) of trifluoroacetic anhydride, and 8.21 g (0.1 mol) of sodium acetate sequentially to a 5 L reaction flask. After the addition is complete, stir well and heat the reaction solution to 40 °C. Maintain the reaction temperature for 24 hours until completion.

[0041] The reaction solution was cooled to room temperature, and 63.59 g (0.6 mol) of solid sodium carbonate was added. The mixture was stirred vigorously for 1 hour. The solution was filtered to remove the solid, and the filtrate was collected. 2 L of petroleum ether was added to the filtrate, and the mixture was cooled to 0°C and kept at this temperature overnight. A solid precipitated, which was then filtered, and the filter cake was collected to obtain 39.66 g (0.111 mol) of a yellow solid product. The yield was 11.1%, and the product purity was 95.69% (HPLC). The NMR data were consistent with those of Example 1.

[0042] Step S2: Preparation of 7-diethylamino-3-thiophenecarboxylocoumarin Add 1 L of dichloroethane, 329.78 g (0.923 mol) of 7-diethylaminocoumarin-3-carboxylic acid trifluoroacetic anhydride, and 79.51 g (0.945 mol) of thiophene sequentially to a 2 L reaction flask, and stir well. Then add 12.01 g (0.09 mol) of aluminum trichloride and stir well. The reaction solution is then heated to 70°C and stirred for 6 hours until the reaction is complete.

[0043] The reaction solution was allowed to cool naturally to room temperature, and 200 mL of saturated sodium bicarbonate solution was added to bring the solution to alkalinity. The mixture was separated, and the organic phase was collected. The organic phase was cooled to 0°C and kept at this temperature for 8 hours to allow crystallization. Solids continued to precipitate, and the solids were filtered. The filter cake was collected to obtain 27.17 g (0.083 mol) of yellow solid product.

[0044] Yield: 8.99%; Product purity: 99.15% (HPLC); NMR data were consistent with those of Example 1.

[0045] As can be seen from Comparative Example 1, when the catalysts in steps S1 and S2 of Example 1 were replaced with other catalysts, the reaction yields decreased sharply. This experimental result confirms that the catalysts selected in this technical solution are unique and highly efficient.

[0046] The above examples are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be used to limit the scope of protection of the present invention. All equivalent transformations or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A method for preparing a 3-arcaryoylcoumarin intermediate compound, characterized in that, The reaction includes step (1) in an inert gas environment, where compound 1 reacts with compound 2 (Missell's acid) and compound 3 (trifluoroacetic anhydride) in a first reaction solvent under the action of a metal catalyst at a reaction temperature of 0–50°C. After the reaction is complete, compound 4 is obtained. The metal catalyst is one or more of sodium trifluoroacetate, potassium trifluoroacetate, lithium trifluoroacetate, cesium trifluoroacetate, or magnesium trifluoroacetate. The molar ratio of the metal catalyst to compound 1 is 0.0001–0.2:

1. The reaction formula is shown below: In the formula, R1, R2, R3 and R4 are independently selected from hydrogen, methyl, ethyl, C3-C8 alkyl, phenyl, diethylamino, dimethylamino, methoxy or ethoxy.

2. The method for preparing the 3-aranylcoumarin intermediate compound according to claim 1, characterized in that, The first reaction solvent is one or more of the following: dichloroethane, ethyl acetate, dichloromethane, acetonitrile, methyl acetate, acetone, butanone, isopropyl acetate, butyl acetate, ethylene glycol diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, chlorobenzene, nitrobenzene, or o-dichlorobenzene.

3. The method for preparing the 3-aranylcoumarin intermediate compound according to claim 1, characterized in that, The molar ratio of compound 1, compound 2 Michaelis acid, and compound 3 trifluoroacetic anhydride is 1:1-5:1-10.

4. The 3-arcaryococoumarin intermediate compound prepared by the method for preparing 3-arcaryococoumarin intermediate compounds according to claim 1, characterized in that, Its structural formula is shown in compound 4: In the formula, R1, R2, R3 and R4 are independently selected from hydrogen, methyl, ethyl, C3-C8 alkyl, phenyl, diethylamino, dimethylamino, methoxy or ethoxy.

5. The method for preparing 3-arcaryococoumarin compounds from the 3-arcaryococoumarin intermediate compound according to claim 4, characterized in that, The reaction also includes step (2), in which compound 4 and compound 5 react in a second reaction solvent under the action of a catalyst at a reaction temperature of -20 to 200°C. After the reaction is complete, compound 6, a 3-aranylcoumarin compound, is obtained. The catalyst is one or more of methanesulfonic acid, trifluoromethanesulfonic acid, p-nitrobenzenesulfonic acid, o-nitrobenzenesulfonic acid, benzenesulfonic acid, or p-methylbenzenesulfonic acid. The molar ratio of the catalyst to compound 4 is 0.0001 to 0.2:

1. The reaction formula is shown below: In the formula, R1, R2, R3 and R4 are independently selected from hydrogen, methyl, ethyl, C3-C8 alkyl, phenyl, diethylamino, dimethylamino, methoxy or ethoxy, and Ar is selected from 2-thienyl, phenyl, 2-furanyl, 2-naphthyl, 4-methoxyphenyl, 4-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-dimethylaminophenyl.

6. The method for preparing 3-arcaryococoumarin compounds from the 3-arcaryococoumarin intermediate compound according to claim 5, characterized in that, The second reaction solvent is one or more of the following: dichloroethane, ethyl acetate, dichloromethane, acetonitrile, methyl acetate, acetone, butanone, isopropyl acetate, butyl acetate, ethylene glycol diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, or dioxane.

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