Process for the preparation of 3,3'-carbonylbis(7-diethylaminocoumarin) compounds

Abstract

3,3'-carbonyl bis(7-diethylaminocoumarin) compound preparation method, including: (1) in inert gas environment, compound 1 with compound 2 mikhailov acid, compound 3 methanesulfonic anhydride in the first reaction solvent, under the action of metal catalyst, the reaction temperature is 0~150 DEG C, reaction, after reaction is completed, compound 4 is obtained;(2) compound 4 and compound 5 in the second reaction solvent, under the action of catalyst, the reaction temperature is-20~200 DEG C, reaction, after reaction is completed, compound 6 3,3'-carbonyl bis(7-diethylaminocoumarin) is obtained.The key raw material of the application is cheap and easy to obtain;The reaction condition is relatively mild, and the operator is friendly, the reaction yield is high, the product purity is high, the production cost is greatly reduced, and the demand of product ton level production can be fully met.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for preparing 3,3'-carbonylbis(7-diethylaminocoumarin) compounds. Background Technology

[0002] Triplete photosensitizers are compounds that possess strong ultraviolet or visible light absorption, efficient intersystem crossing (ISC), and long-lived triplet states. Due to their unique photophysical and photochemical properties, these compounds have attracted widespread attention in the chemical community and are widely used in photodynamic therapy (PDT), photocatalytic water splitting for hydrogen production, dye-sensitized solar cells, triplet-tript annihilation (TTA) upconversion, photocatalytic organic chemical reactions, and oxygen sensing.

[0003] Traditional triplet photosensitizers primarily rely on the heavy atom effect of heavy atoms such as platinum, iridium, and ruthenium to enhance the spin-orbit coupling (SOC) effect of molecules, thereby increasing the triplet yield. However, the high pollution and cost of heavy atoms, due to their high spin-orbit coupling coefficients, often increase the intersystem crossing rate of the triplet state back to the ground state, thus shortening the triplet lifetime. This also leads to problems such as high synthesis costs, high biotoxicity, and compound instability, thus affecting the application and development of triplet photosensitizers in the PDT field.

[0004] Heavy atom-free triplet photosensitizers typically possess advantages such as low synthesis cost, low toxicity, and long triplet lifetime, making them a popular research direction in the field of triplet photosensitizers. Ketocoumarins are an important class of heavy atom-free triplet photosensitizers, exhibiting a triplet-triplet annihilation upconversion quantum yield of over 10%. 3,3'-carbonylbis(7-diethylaminocoumarin) (CAS; 63226-13-1, structure shown below) is one of the most widely used heavy atom-free triplet photosensitizers among these ketocumaruin classes.

[0005]

[0006] The only practically applicable synthetic route for 3,3'-carbonylbis(7-diethylaminocoumarin) has been reported so far, as described in the New Journal of Chemistry (2019), 43(23), 9090-9105:

[0007]

[0008] The route employs a three-step synthesis method. In the first step, citric acid is used as the starting material, and under the action of fuming sulfuric acid, it is decarboxylated and oxidized to obtain 1,3-propanone dicarboxylic acid. In the second step, 1,3-propanone dicarboxylic acid is used as the starting material and reacted with methanol under sulfuric acid catalysis to obtain dimethyl 1,3-propanone dicarboxylic acid. In the third step, dimethyl 1,3-propanone dicarboxylic acid is used as the starting material and reacted with 4-(diethylamino)salicylaldehyde through ring-closing condensation to obtain 3,3'-carbonylbis(7-diethylaminocoumarin).

[0009] This method suffers from four serious problems when scaled up to kilogram levels or higher: First, the first step uses more than two equivalents of fuming sulfuric acid as both a decarboxylating agent and an oxidizing agent. Fuming sulfuric acid is extremely dangerous and highly volatile; the sulfur trioxide it releases forms acid mist upon contact with moisture in the air, which is highly corrosive. The reaction environment is harsh and unfriendly to operators, failing to meet the requirements of green production. Second, the post-reaction treatment in the first step requires a large amount of ice water to quench the reaction, generating a large amount of acidic wastewater, also failing to meet green production requirements. Third, the ring-closing reaction in the third step has low efficiency, with a yield of only 70%, resulting in high production costs and poor economic efficiency. Fourth, the reaction involves three steps, which is lengthy, cumbersome, and costly, making the reaction route uneconomical. These problems severely limit the further application of this process and make ton-scale scaling up of this product extremely difficult.

[0010] To address the problems of high reagent hazard, poor process safety, excessive waste, operator inconvenience, and poor economy associated with existing processes for synthesizing 3,3'-carbonylbis(7-diethylaminocoumarin), it is of great significance to find a synthetic method for 3,3'-carbonylbis(7-diethylaminocoumarin) that features a reasonable route design, fewer reaction steps, safe and readily available raw materials, high process safety, less waste, operator-friendly design, and high economic efficiency. Summary of the Invention

[0011] In view of the problems existing in the prior art, the present invention develops a method for preparing 3,3'-carbonyl bis(7-diethylaminocoumarin) compounds. This preparation method has the advantages of readily available raw materials, low cost, ease of industrial-scale production, high yield, and high purity.

[0012] One of the technical problems to be solved by the present invention is to provide a method for preparing 3,3'-carbonylbis(7-diethylaminocoumarin) compounds, comprising:

[0013] (1) Under an inert gas environment, compound 1 reacts with compound 2 (Mischel acid) and compound 3 (methanesulfonic anhydride) in the first reaction solvent under the action of a metal catalyst at a reaction temperature of 0–150 °C. After the reaction is complete, compound 4 is obtained.

[0014] (2) Compound 4 and compound 5 reacted in the second reaction solvent under the action of a catalyst at a reaction temperature of -20 to 200℃. After the reaction was complete, compound 6, 3,3'-carbonylbis(7-diethylaminocoumarin), was obtained. The reaction formula is shown below:

[0015] .

[0016] 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.

[0017] In a preferred embodiment of the present invention, the metal catalyst is one or more of sodium methanesulfonate, potassium methanesulfonate, cesium methanesulfonate, magnesium methanesulfonate, or calcium methanesulfonate.

[0018] In a preferred embodiment of the present invention, the molar ratio of compound 1, compound 2 and compound 3 is 1:1 to 5:1 to 10.

[0019] In a preferred embodiment of the present invention, the molar ratio of the metal catalyst to compound 1 is 0.0001 to 0.2:1.

[0020] In a preferred embodiment of the present invention, the second reaction solvent 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.

[0021] 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.

[0022] In a preferred embodiment of the present invention, the molar ratio of the catalyst to compound 4 is 0.0001 to 0.2:1. Beneficial effects

[0023] The key raw materials used in the synthetic route of 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 yield is high, the product purity is high, which greatly reduces the production cost and can fully meet the needs of production at the ton level or above. Detailed Implementation

[0024] 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.

[0025] Unless otherwise specified, all materials and reagents used in the following examples are commercially available. Example 1

[0026] Step S1: Preparation of 7-diethylaminocoumarin-3-carboxylic acid methanesulfonic anhydride

[0027] 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, 191.61 g (1.1 mol) of methanesulfonic anhydride, and 11.81 g (0.1 mol) of sodium methanesulfonate sequentially to a 5 L reaction flask. After the addition is complete, stir well and heat the reaction solution to 100 °C. Maintain the reaction temperature for 6 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 solid was filtered off, 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 316.96 g (0.934 mol) of yellow solid product. The yield was 93.4%, and the product purity was 98.35% (HPLC). NMR data: 1H NMR (400 MHz, CDCl3): δ 8.13 (s, 1H), 7.32 (d, 1H), 6.60 (d, 1H), 6.48 (d, 1H), 3.48 (q, 4H), 3.40 (s, 3H), 1.23 (t, 6H).

[0029] Step S2: Preparation of 3,3'-carbonylbis(7-diethylaminocoumarin)

[0030] Add 1 L of dichloroethane, 316.96 g (0.934 mol) of 7-diethylaminocoumarin-3-carboxylic acid methanesulfonic anhydride, and 207.49 g (0.955 mol) of 7-diethylaminocoumarin sequentially to a 2 L reaction flask, and 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.

[0031] 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 420.46 g (0.913 mol) of yellowish-brown solid product.

[0032] Yield: 97.7%, overall yield of the two-step reaction: 91.3%, product purity: 99.34% (HPLC); NMR data: 1 H NMR (400MHz, CDCl3): δ 8.16 (s,2H), 7.38 (d, 2H), 6.61 (d, 2H), 6.49 (s,2H), 3.47(q,8H), 1.25(t,12H). Example 2

[0033] Step S1: Preparation of 7-diethylaminocoumarin-3-carboxylic acid methanesulfonic anhydride

[0034] Maintaining a slight positive nitrogen pressure, add 2 L of dichloroethane, 193.24 g (1.0 mol) of 4-(diethylamino)salicylaldehyde, 216.19 g (1.5 mol) of Michaelis-Menten acid, 209.03 g (1.2 mol) of methanesulfonic anhydride, and 2.28 g (0.01 mol) of cesium methanesulfonate 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.

[0035] 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 that temperature overnight. A large amount of solid precipitated. The solid was filtered, and the filter cake was collected to obtain 320.02 g (0.943 mol) of a yellow solid product. The yield was 94.3%, and the product purity was 98.55% (HPLC).

[0036] Step S2: Preparation of 3,3'-carbonylbis(7-diethylaminocoumarin)

[0037] Add 1 L of dichloroethane, 320.02 g (0.943 mol) of 7-diethylaminocoumarin-3-carboxylic acid methanesulfonic anhydride, and 205.32 g (0.945 mol) of 7-diethylaminocoumarin sequentially to a 2 L reaction flask. After the addition is complete, stir well. Then add 2.88 g (0.03 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.

[0038] 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 300.88 g (0.919 mol) of yellow solid product.

[0039] Yield: 97.5%, overall yield of the two-step reaction: 91.9%, product purity: 99.04% (HPLC). Example 3

[0040] Step S1: Preparation of 7-dimethylaminocoumarin-3-carboxylic acid methanesulfonic anhydride

[0041] 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, 435.47 g (2.5 mol) of methanesulfonic anhydride, and 2.30 g (0.01 mol) of calcium methanesulfonate sequentially to a 5 L reaction flask. After the addition is complete, stir well and heat the reaction solution to 80 °C. Maintain the reaction temperature for 6 hours until completion.

[0042] 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 that temperature overnight. A large amount of solid precipitated. The solid was filtered, and the filter cake was collected to obtain 267.21 g (0.911 mol) of a yellow solid product. The yield was 91.1%, and the product purity was 98.52% (HPLC).

[0043] Step S2: Preparation of 3,3'-carbonylbis(7-diethylaminocoumarin)

[0044] Add 1 L of 2-methyltetrahydrofuran, 267.21 g (0.911 mol) of 7-dimethylaminocoumarin-3-carboxylic acid methanesulfonic anhydride, and 962.51 g (4.43 mol) of 7-diethylaminocoumarin 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.

[0045] 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 259.59 g (0.885 mol) of yellow solid product.

[0046] Yield: 97.1%, overall yield of the two-step reaction: 88.5%, product purity: 99.21% (HPLC).

[0047] Comparative Example 1

[0048] Step S1: Preparation of 7-diethylaminocoumarin-3-carboxylic acid methanesulfonic anhydride

[0049] Maintaining a slight positive pressure of nitrogen, add 2 L of dichloroethane, 193.24 g (1.0 mol) of 4-(diethylamino)salicylaldehyde, 216.19 g (1.5 mol) of Michaelis-Menten acid, 209.03 g (1.2 mol) of methanesulfonic anhydride, and 1.92 g (0.01 mol) of cesium 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.

[0050] 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 that temperature overnight. A small amount of solid precipitated; this was filtered, and the filter cake was collected to obtain 45.81 g (0.135 mol) of a yellow solid product. The yield was 13.5%, and the product purity was 95.11% (HPLC).

[0051] Step S2: Preparation of 3,3'-carbonylbis(7-diethylaminocoumarin)

[0052] Add 1 L of dichloroethane, 320.02 g (0.943 mol) of 7-diethylaminocoumarin-3-carboxylic acid methanesulfonic anhydride, and 205.32 g (0.945 mol) of 7-diethylaminocoumarin sequentially to a 2 L reaction flask, and stir well. Then add 4.01 g (0.03 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.

[0053] 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 small amount of solid continued to precipitate. The solid was filtered, and the filter cake was collected to obtain 25.86 g (0.079 mol) of yellow solid product.

[0054] Yield: 7.45%, product purity: 97.13% (HPLC).

[0055] 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.

[0056] 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

A method for preparing a 1,3'-carbonylbis(7-diethylaminocoumarin) compound, characterized in that, include: (1) In an inert gas environment, compound 1 reacts with compound 2 Michaelis acid and compound 3 methanesulfonic anhydride in the first reaction solvent under the action of a metal catalyst at a reaction temperature of 0-150℃. After the reaction is complete, compound 4 is obtained. The metal catalyst is one or more of sodium methanesulfonate, potassium methanesulfonate, cesium methanesulfonate, magnesium methanesulfonate or calcium methanesulfonate. The molar ratio of the metal catalyst to compound 1 is 0.0001-0.2:

1. (2) Compound 4 and Compound 5 react in the 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 3,3'-carbonylbis(7-diethylaminocoumarin) 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: 。 2. The method for preparing the 3,3'-carbonylbis(7-diethylaminocoumarin) 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 3,3'-carbonylbis(7-diethylaminocoumarin) compound according to claim 1, characterized in that, The molar ratio of compound 1, compound 2 and compound 3 is 1: 1-5: 1-10.

4. The method for preparing the 3,3'-carbonylbis(7-diethylaminocoumarin) compound according to claim 1, 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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