A method for continuous flow synthesis of 1-(1,10-phenanthroline-2-yl)ethanone

Abstract

The invention provides a method for synthesizing 1-(1,10-phenanthroline-2-yl)ethanone by continuous flow reaction. 1,10-phenanthroline monohydrate is used as a raw material, reaction conditions are precisely controlled under specific reaction raw materials, solvents and continuous flow control reaction parameters for reaction, reaction efficiency and yield are high, operation is simple, environmental protection and safety are achieved, and the method has the prospect of industrialized scale-up production.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for continuous flow synthesis of 1-(1,10-phenanthroline-2-yl)ethanone. Background Art

[0002] 1-(1,10-Phenanthrolin-2-yl)ethanone, English name: 1-(1,10-Phenanthrolin-2-yl)ethanone; CAS: 72404-92-3, is a very important optoelectronic material. The development of its safe and efficient production process is of great significance. At present, there are several reports on the synthesis process of 1-(1,10-phenanthroline-2-yl) ethyl ketone at home and abroad; for example, the Chinese patent application with publication number CN110003203A discloses that 1,10-phenanthroline is used as an initiator and a target product is obtained by side chain alkylation. Due to its low reaction selectivity, the yield of the unilaterally substituted alkylated phenanthroline product to be obtained is very low, and the product is complex and difficult to separate; the Chinese patent application with publication number CN112961154A discloses that 8-aminoquinoline is used as a raw material for an addition reaction to obtain 4-oxo-3-(quinoline-8-amino) valeraldehyde, which is then subjected to a cyclization reaction to obtain 2-acetyl-1,2-dihydrophenanthroline, and then an oxidation reaction is performed to obtain 1-(1,10-phenanthroline-2-yl) ethyl ketone. This method has a long route and a long reaction time. The Chinese patent application with publication number CN102040608A discloses that 2-cyano-1,10-phenanthroline is suspended in toluene as a raw material, trimethylaluminum toluene solution is added dropwise at -78°C, and then the temperature is slowly raised to room temperature. After stirring at room temperature for 12 hours, a small amount of water is added dropwise to the reaction mixture in an ice-water bath, and a yellow precipitate appears. The mixture is then extracted with dilute hydrochloric acid. The combined water layers are adjusted to alkalinity with solid potassium hydroxide, and the resulting precipitate is filtered, dried, and then purified by a basic alumina column with a yield of 60%. This route has strict temperature requirements, the reaction time is too long, and post-processing is difficult to achieve scale-up production.

[0003] It can be seen that the existing 1-(1,10-phenanthroline-2-yl)ethanone synthesis processes are all kettle-type synthesis processes, which have the disadvantages of complex routes, long reaction time, low yield, and difficulty in industrial scale-up production. Continuous flow chemistry, also known as flow chemistry, refers to the technology of transporting materials by pumps and conducting chemical reactions in a continuous flow mode. Thanks to the advantages of continuous flow reactions (1) rapid mass and heat transfer; (2) precise parameter control and good reaction selectivity, especially suitable for inhibiting cascade side reactions; (3) continuous operation and high time and space efficiency; (4) easy automation; (5) safety, etc., continuous flow reactions have received increasing attention in recent years.

[0004] However, continuous flow reactions require precise control, and multiple factors such as material quantity, reaction temperature, and time will affect the reaction results. Therefore, conventional kettle reaction processes still have difficulties when applied to continuous flow reactions. In order to quickly, safely, and efficiently scale up the production of 1-(1,10-phenanthroline-2-yl)ethanone, it is of great significance to provide a process for synthesizing 1-(1,10-phenanthroline-2-yl)ethanone by continuous flow reaction. Summary of the invention

[0005] In order to solve the problems of the existing kettle-type synthesis of 1-(1,10-phenanthroline-2-yl)ethanone, such as complex process route, long reaction time, low yield, difficulty in industrialized scale-up production, etc., the present invention provides a continuous flow synthesis process of 1-(1,10-phenanthroline-2-yl)ethanone.

[0006] The present invention provides a method for continuous flow synthesis of 1-(1,10-phenanthroline-2-yl)ethanone, comprising the following steps:

[0007] (1) Synthesis of 1,10-phenanthroline-1-oxide: 1,10-phenanthroline or its hydrate is dissolved in an organic solvent to obtain an organic solution A, and the organic solution A is introduced into a continuous flow reactor I through a metering pump 1 and an oxidant solution is introduced into a continuous flow reactor I through a metering pump 2. The continuous flow reactor I is kept at 85 to 95° C. for reaction to obtain 1,10-phenanthroline-1-oxide;

[0008] (2) Synthesis of 1,10-phenanthroline-2-carbonitrile: 1,10-phenanthroline-1-oxide and alkali are added with water to prepare an alkaline aqueous solution B, and at the same time, a sodium cyanide aqueous solution is passed through a metering pump 3 and dichloromethane or dichloroethane is passed through a metering pump 4 into a mixing module m to obtain a reaction solution 1 after mixing;

[0009] The reaction solution 1 is passed into the mixing module n, and the aqueous solution B is passed into the mixing module n through the metering pump 5, and then mixed to obtain the reaction solution 2;

[0010] The reaction solution 2 is introduced into the continuous flow reactor II, and at the same time, a dichloromethane or dichloroethane solution of an acyl chloride activator is introduced into the continuous flow reactor II through a metering pump 6 to react for at least 10 minutes to obtain 1,10-phenanthroline-2-carbonitrile;

[0011] (3) Synthesis of 1-(1,10-phenanthroline-2-yl)ethanone: 1,10-phenanthroline-2-carbonitrile is dissolved in tetrahydrofuran or dichloromethane to obtain an organic solution B, and the organic solution B is precooled by a metering pump 7 through a precooling module a and then introduced into a reactor III. At the same time, an organic solution of a Grignard reagent is precooled by a metering pump 8 through a precooling module b and then introduced into a reactor III to react and obtain a reaction solution. The flow rate ratio of the metering pump 7 to the metering pump 8 is (3.5-5.6):1;

[0012] The reaction solution is introduced into a continuous flow quenching reactor, and at the same time, an aqueous hydrochloric acid solution is introduced into the continuous flow quenching reactor through a metering pump 9, and 1-(1,10-phenanthroline-2-yl)ethanone is obtained after quenching the reaction.

[0013] Furthermore, the organic solvent in step (1) is acetic acid, and the oxidant solution is an aqueous solution of hydrogen peroxide.

[0014] Furthermore, the concentration of 1,10-phenanthroline or its hydrate in the organic solution A is 9-17%, the aqueous hydrogen peroxide solution is 30%-50% aqueous hydrogen peroxide solution, and the flow rate ratio of metering pump 1 to metering pump 2 is (6-7)x:1, x=y / z, y is the ratio of the concentration of the aqueous hydrogen peroxide solution to 30%, and z is the ratio of the concentration of 1,10-phenanthroline or its hydrate in the organic solution A to 16.67%;

[0015] Preferably, the flow rate of the metering pump 1 is 6 ml / min to 900 ml / min, and the flow rate of the metering pump 2 is 1 ml / min to 150 ml / min.

[0016] Furthermore, the reaction conditions of step (1) are: back pressure 0.1-0.2 MPa, reaction time 50-70 min.

[0017] Furthermore, the base in step (2) is any one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; the molar ratio of 1,10-phenanthroline-1-oxide, water, and base in the aqueous solution B is 1:5:(18-19); the concentration of sodium cyanide in the sodium cyanide aqueous solution is 7.4-16.7%; the concentration of benzoyl chloride in the dichloromethane or dichloroethane solution of benzoyl chloride is 25-35%; and the acyl chloride activator is benzoyl chloride.

[0018] Furthermore, in step (2), the flow rate ratio of the metering pump 3 to the metering pump 4 is 1:(1.5-2); the flow rate of the metering pump 5 is 1:(1.6-2.1) to the sum of the flow rates of the metering pumps 3 and 4; the flow rate of the metering pump 6 is 1:(11.5-12.0) to the sum of the flow rates of the metering pumps 3, 4 and 5;

[0019] Preferably, the flow rate of the metering pump 3 is 1 ml / min to 150 ml / min, the flow rate of the metering pump 4 is 1.7 ml / min to 200 ml / min, the flow rate of the metering pump 5 is 1.5 ml / min to 200 ml / min, and the flow rate of the metering pump 6 is 0.3 ml / min to 50 ml / min.

[0020] Furthermore, in step (2), the mixing conditions of the mixing module m are 0-40° C. for 1-3 min, and the mixing conditions of the mixing module n are 0-40° C. for 1-3 min; and the reaction conditions are 20-50° C. for 11-18 min.

[0021] Furthermore, the concentration of 1,10-phenanthroline-2-carbonitrile in the organic solution B of step (3) is 6.5-7.5%, the organic solution of the Grignard reagent is a tetrahydrofuran solution of methylmagnesium chloride, methylmagnesium bromide or methylmagnesium iodide, with a concentration of 2.5-3.5M / L; and the hydrochloric acid aqueous solution is a 2.5% hydrochloric acid aqueous solution.

[0022] Furthermore, in step (3), the flow rate ratio of the metering pump 7 and the metering pump 9 is (0.7-1.3):1;

[0023] Preferably, the flow rate of the metering pump 7 is 4 ml / min to 200 ml / min, the flow rate of the metering pump 8 is 1 ml / min to 100 ml / min, and the flow rate of the metering pump 9 is 4 ml / min to 200 ml / min.

[0024] Furthermore, the precooling temperature of the precooling module a in step (3) is -5 to 5°C, the precooling time is 0.5 to 1.5 min, and the cooling temperature of the precooling module b is -10 to 0°C, the precooling time is 0.5 to 1.5 min;

[0025] The reaction conditions are: 0-10°C for 20-30 min;

[0026] The quenching reaction condition is quenching at 0-40° C. for 2-3.5 min.

[0027] Beneficial effects of the invention: The method for synthesizing 1-(1,10-phenanthroline-2-yl)ethanone adopts a continuous flow reactor, takes 1,10-phenanthroline monohydrate as a raw material, and accurately controls the reaction conditions under specific continuous flow control parameters for reaction, has high reaction efficiency and yield, is simple to operate, is environmentally friendly and safe, and has the prospect of industrialized scale-up production.

[0028] The structure of "1,10-phenanthroline" of the present invention:

[0029] Structure of "1,10-phenanthroline-1-oxide":

[0030] The structure of "1,10-phenanthroline-2-carbonitrile":

[0031] The structure of "1-(1,10-phenanthroline-2-yl)ethanone":

[0032] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0033] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 It is a schematic diagram of the reaction flow of the present invention. DETAILED DESCRIPTION

[0035] The raw materials and equipment used in the present invention are all known products, which are obtained by purchasing commercially available products.

[0036] The reaction process of the present invention is as follows Figure 1 shown.

[0037] Example 1. Synthesis of 1-(1,10-phenanthroline-2-yl)ethanone of the present invention

[0038] 1. Synthesis of 1,10-phenanthroline-1-oxide

[0039] Method 1:

[0040] Solution A: a mixed solution of 50 g of 1,10-phenanthroline monohydrate and 250 g of acetic acid, connected to metering pump 1;

[0041] Solution B: 30% hydrogen peroxide 50g (45ml) connected to metering pump 2;

[0042] The specific parameters of the module are as follows:

[0043] Continuous flow reactor I, circulation temperature reaches 90°C and reaches stability, volume: 420 mL;

[0044] The specific operations are as follows:

[0045] The automatic feeding system was turned on, and solution A and solution B were fed by metering pumps 1 and 2 respectively, with a flow rate of solution A = 6 ml / min and a flow rate of solution B = 1 ml / min; the two streams of materials entered the continuous flow reactor I and began to slowly back-pressure, and the back-pressure reached 0.1-0.2 MPa. After staying for 60 minutes, they began to be collected in the concentration kettle; after the operation was completed, the reaction was concentrated under reduced pressure at P = 8 mmHg, T = 60°C to obtain 51 g of the target product 1,10-phenanthroline, 1-oxide, with an HPLC purity of 90% and a yield of 94%.

[0046] Method 2:

[0047] Solution A: a mixed solution of 50 g of 1,10-phenanthroline monohydrate and 500 g of acetic acid, connected to metering pump 1;

[0048] Solution B: 30% hydrogen peroxide 50g connected to metering pump 2;

[0049] The specific parameters of the module are as follows:

[0050] The continuous flow reactor 1 was set, the circulation temperature reached 90°C and reached stability, the volume was 740 mL;

[0051] The specific operations are as follows:

[0052] The automatic feeding system was turned on, and solution A and solution B were fed by metering pumps 1 and 2 respectively, with a flow rate of solution A = 11.3 ml / min and a flow rate of solution B = 1 ml / min; the two streams of materials entered the continuous flow reactor 1 and began to be slowly back-pressurized to 0.1-0.2 MPa, and after staying for 60 minutes, they were collected in the concentration kettle; after the operation was completed, the reaction was concentrated under reduced pressure at P = 8 mmHg, T = 60°C to obtain 51 g of the target product 1,10-phenanthroline, 1-oxide, with an HPLC purity of 89% and a yield of 94%.

[0053] Method 3:

[0054] Solution A: a mixed solution of 50 g of 1,10-phenanthroline monohydrate and 250 g of acetic acid, connected to metering pump 1;

[0055] Solution B: 30% hydrogen peroxide 50g connected to metering pump 2;

[0056] The specific parameters of the module are as follows:

[0057] Continuous flow reactor 1, circulation temperature reaches 90 °C and reaches stability, volume 350 mL;

[0058] The specific operations are as follows:

[0059] The automatic feeding system was turned on, and solution A and solution B were fed by metering pumps 1 and 2 respectively, with a flow rate of solution A = 6 ml / min and a flow rate of solution B = 1 ml / min; the two streams of materials entered the continuous flow reactor 1 and began to be slowly back-pressurized to 0.1-0.2 MPa, and after staying for 50 minutes, they were collected in the concentration kettle; after the operation was completed, the reaction was concentrated under reduced pressure at P = 8 mmHg, T = 60°C to obtain 46 g of the target product 1,10-phenanthroline, 1-oxide, with an HPLC purity of 86% and a yield of 85%.

[0060] Method 4:

[0061] Solution A: a mixed solution of 50 g of 1,10-phenanthroline monohydrate and 250 g of acetic acid, connected to metering pump 1;

[0062] Solution B: 50% hydrogen peroxide 28.3g connected to metering pump 2;

[0063] The specific parameters of the module are as follows:

[0064] Continuous flow reactor 1, the circulation temperature reached 90 °C and reached stability, the volume was 714 mL;

[0065] The specific operations are as follows:

[0066] The automatic feeding system was turned on, and solution A and solution B were fed by metering pumps 1 and 2 respectively, with a flow rate of solution A = 10.9 ml / min and a flow rate of solution B = 1 ml / min; the two streams of materials entered the continuous flow reactor 1 and began to be slowly back-pressurized to 0.1-0.2 MPa, and after staying for 60 minutes, they were collected in the concentration kettle; after the operation was completed, the reaction was concentrated under reduced pressure at P = 8 mmHg, T = 60°C to obtain 51.7 g of the target product 1,10-phenanthroline, 1-oxide, with an HPLC purity of 92% and a yield of 95%.

[0067] Method 5:

[0068] Solution A: a mixed solution of 50 g of 1,10-phenanthroline monohydrate and 250 g of acetic acid, with 0.5 g of p-toluenesulfonic acid as a catalyst added to accelerate the reaction, connected to metering pump 1;

[0069] Solution B: 30% hydrogen peroxide 50g connected to metering pump 2;

[0070] The specific parameters of the module are as follows:

[0071] Continuous flow reactor 1, circulation temperature reached 90 °C and reached stability, 420 mL;

[0072] The specific operations are as follows:

[0073] The automatic feeding system was turned on, and solution A and solution B were fed by metering pumps 1 and 2 respectively, with a flow rate of solution A = 6 ml / min and a flow rate of solution B = 1 ml / min; the two streams of materials entered the continuous flow reactor 1 and began to be slowly back-pressurized to 0.1-0.2 MPa, and after staying for 60 minutes, they began to be collected in the concentration kettle; after the operation was completed, the reaction was concentrated under reduced pressure at P = 8 mmHg, T = 60°C to obtain 51.7 g of the target product 1,10-phenanthroline, 1-oxide, with an HPLC purity of 90% and a yield of 95%.

[0074] Method 6 (scale-up reaction):

[0075] Solution A: a mixed solution of 250 kg of 1,10-phenanthroline monohydrate and 1100 kg of acetic acid, connected to metering pump 1;

[0076] Solution B: 30% hydrogen peroxide 235 kg connected to metering pump 2;

[0077] The specific parameters of the module are as follows:

[0078] Continuous flow reactor 1, circulation temperature reaches 90°C and reaches stability, volume: 6.3L;

[0079] The specific operations are as follows:

[0080] The automatic feeding system was turned on, and solution A and solution B were fed by metering pumps 1 and 2 respectively, with a flow rate of solution A = 900 ml / min and a flow rate of solution B = 150 ml / min; the two streams of materials entered the continuous flow reactor 1 and began to be slowly back-pressurized to 0.1-0.2 MPa, and after staying for 60 minutes, they began to be collected in the concentration kettle; after the operation was completed, the reaction was concentrated under reduced pressure at P = 8 mmHg, T = 60°C to obtain 232.6 kg of the target product 1,10-phenanthroline, 1-oxide, with an HPLC purity of 90% and a yield of 94%.

[0081] 2. Synthesis of 1,10-phenanthroline-2-carbonitrile

[0082] Method 1:

[0083] Solution A': 16g sodium cyanide + 80g aqueous solution;

[0084] Solution B': 200 g dichloromethane;

[0085] Solution C': 16g 1,10-phenanthroline-1-oxide + 80g water + 10% (sodium hydroxide) solution, adjust the pH of the solution to alkaline;

[0086] Solution D': 11.5g benzoyl chloride + 25g dichloromethane solution;

[0087] The module parameters are set as follows:

[0088] Mixing module 1 temperature control 0 ~ 40 ℃, module volume: 20mL;

[0089] Mixing module 2 temperature control 0 ~ 40 ℃, module volume: 35mL;

[0090] The temperature of the mixed reaction module is controlled at 20-50°C, and the module volume is 200mL.

[0091] The specific operations are as follows:

[0092] The automatic feeding system was turned on, and solution A' and solution B' were fed by metering pumps respectively. The flow rate of solution A' was 3.6 mL / min, and the flow rate of solution B' was 6.4 mL / min. The two streams of materials passed through mixing module 1. After staying for 2 minutes, the materials entered mixing module 2 and metering pump 3 was turned on at the same time. The flow rate of solution C' was 5.4 mL / min. After staying for 2.3 minutes, the materials entered the mixed reaction module and metering pump 4 was turned on at the same time. The flow rate of solution D' was 1.3 mL / min. After staying for 12 minutes, the outflowing reaction liquid was post-treated: standing for phase separation and extraction and washing (until the cyanide test paper test was negative); the organic phase was concentrated under reduced pressure, ethyl acetate was added for crystallization, and filtration was performed to obtain 13.38 g of the target product 1,10-phenanthroline-2-carbonitrile, with an HPLC purity of 95% and a yield of 80%.

[0093] Method 2:

[0094] Solution A': 16g sodium cyanide + 80g aqueous solution;

[0095] Solution B': 200 g ethylene dichloride;

[0096] Solution C': 16g 1,10-phenanthroline-1-oxide + 80g water + 10% (sodium hydroxide) solution, adjust the pH of the solution to alkaline;

[0097] Solution D': 11.5g benzoyl chloride + 25g dichloroethane solution;

[0098] The module parameters are set as follows:

[0099] Mixing module 1 temperature control 0 ~ 40 ℃, module volume: 20mL;

[0100] Mixing module 2 temperature control 0 ~ 40 ℃, module volume: 35mL;

[0101] The temperature of the mixed reaction module is controlled at 20-50°C, and the module volume is 200mL.

[0102] The specific operations are as follows:

[0103] The automatic feeding system was turned on, and solution A' and solution B' were fed by metering pumps respectively. The flow rate of solution A' was 3.6 mL / min, and the flow rate of solution B' was 6.4 mL / min. The two streams of materials passed through mixing module 1. After staying for 2 minutes, the materials entered mixing module 2 and metering pump 3 was turned on at the same time. The flow rate of solution C' was 5.4 mL / min. After staying for 2.3 minutes, the materials entered the mixed reaction module and metering pump 4 was turned on at the same time. The flow rate of solution D' was 1.3 mL / min. After staying for 12 minutes, the outflowing reaction liquid was post-treated: standing for phase separation and extraction and washing (until the cyanide test paper test was negative); the organic phase was concentrated under reduced pressure, ethyl acetate was added for crystallization, and filtration was performed to obtain 13.38 g of the target product 1,10-phenanthroline-2-carbonitrile, with an HPLC purity of 95% and a yield of 80%.

[0104] Method 3:

[0105] Solution A': 16g sodium cyanide + 80g aqueous solution;

[0106] Solution B': 200 g dichloromethane;

[0107] Solution C': 16g 1,10-phenanthroline-1-oxide + 80g water + 10% (sodium hydroxide) solution, adjust the pH of the solution to alkaline;

[0108] Solution D': 11.5g benzoyl chloride + 25g dichloromethane solution;

[0109] The module parameters are set as follows:

[0110] Mixing module 1 temperature control 0 ~ 40 ℃, module volume: 20mL;

[0111] Mixing module 2 temperature control 0 ~ 40 ℃, module volume: 35mL;

[0112] The temperature of the mixed reaction module is controlled at 20-50°C, and the module volume is 300mL.

[0113] The specific operations are as follows:

[0114] The automatic feeding system was turned on, and solution A' and solution B' were fed by metering pumps respectively. The flow rate of solution A' was 3.6 mL / min, and the flow rate of solution B' was 6.4 mL / min. The two streams of materials passed through mixing module 1. After staying for 2 minutes, the materials entered mixing module 2 and metering pump 3 was turned on at the same time. The flow rate of solution C' was 5.4 mL / min. After staying for 2.3 minutes, the materials entered the mixed reaction module and metering pump 4 was turned on at the same time. The flow rate of solution D' was 1.3 mL / min. After staying for 18 minutes, the outflowing reaction liquid was post-treated: standing for phase separation and extraction and washing (until the cyanide test paper test was negative); the organic phase was concentrated under reduced pressure, ethyl acetate was added for crystallization, and filtration was performed to obtain 13.38 g of the target product 1,10-phenanthroline-2-carbonitrile, with an HPLC purity of 95% and a yield of 80%.

[0115] Method 4 (expanded reaction):

[0116] Solution A': 1kg sodium cyanide + 8kg aqueous solution;

[0117] Solution B': 20 kg dichloromethane;

[0118] Solution C': 1.6 kg 1,10-phenanthroline-1-oxide + 8.0 kg water + 10% (sodium hydroxide) solution, the solution is adjusted to alkaline pH;

[0119] Solution D': 1.15 kg benzoyl chloride + 2.5 kg dichloromethane solution;

[0120] The module parameters are set as follows:

[0121] Mixing module 1 temperature control 0 ~ 40 ° C, module volume: 100 mL;

[0122] Mixing module 2 temperature control 0 ~ 40 ℃, module volume: 150mL;

[0123] The temperature of the mixed reaction module is controlled at 20-50°C, and the module volume is 500mL.

[0124] The specific operations are as follows:

[0125] The automatic feeding system was turned on, and solution A' and solution B' were fed by metering pumps respectively. The flow rate of solution A' was 18 mL / min, and the flow rate of solution B' was 32 mL / min. The two streams of materials passed through mixing module 1. After staying for 2 minutes, the materials entered mixing module 2 and metering pump 3 was turned on at the same time. The flow rate of solution C' was 27 mL / min. After staying for 2.3 minutes, the materials entered the mixed reaction module and metering pump 4 was turned on at the same time. The flow rate of solution D' was 6.5 mL / min. After staying for 12 minutes, the outflowing reaction liquid was post-treated: standing for phase separation and extraction and washing (until the cyanide test paper test was negative); the organic phase was concentrated under reduced pressure, ethyl acetate was added for crystallization, and filtration was performed to obtain 0.924 kg of the target product 1,10-phenanthroline-2-carbonitrile, with an HPLC purity of 95% and a yield of 88%.

[0126] Method 5 (expanded reaction):

[0127] Solution A': 50kg sodium cyanide + 625kg aqueous solution;

[0128] Solution B': 1560 kg dichloromethane;

[0129] Solution C': 125kg 1,10-phenanthroline-1-oxide + 625kg water + 10% (sodium hydroxide) solution, the solution is adjusted to alkaline pH;

[0130] Solution D': 89.8 kg benzoyl chloride + 195 kg dichloromethane solution;

[0131] The module parameters are set as follows:

[0132] Mixing module 1 temperature control 0 ~ 40 ° C, module volume: 200 mL;

[0133] Mixing module 2 temperature control 0 ~ 40 ℃, module volume: 350mL;

[0134] The temperature of the mixed reaction module is controlled at 20-50°C, and the module volume is 2L.

[0135] The specific operations are as follows:

[0136] The automatic feeding system was turned on, and solution A' and solution B' were fed by metering pumps respectively. The flow rate of solution A' was 36 mL / min, and the flow rate of solution B' was 64 mL / min. The two streams of materials passed through mixing module 1. After staying for 2 minutes, the materials entered mixing module 2 and metering pump 3 was turned on at the same time. The flow rate of solution C' was 54 mL / min. After staying for 2.3 minutes, the materials entered the mixed reaction module and metering pump 4 was turned on at the same time. The flow rate of solution D' was 13 mL / min. After staying for 12 minutes, the outflowing reaction liquid was post-treated: standing for phase separation and extraction and washing (until the cyanide test paper test was negative); the organic phase was concentrated under reduced pressure, ethyl acetate was added for crystallization, and filtration was performed to obtain 46.73 kg of the target product 1,10-phenanthroline-2-carbonitrile, with an HPLC purity of 95% and a yield of 89%.

[0137] 3. Synthesis of 1-(1,10-phenanthroline-2-yl)ethanone

[0138] Method 1:

[0139] Solution A: 50 g of 1,10-phenanthroline-2-carbonitrile and 675 g of tetrahydrofuran were mixed to obtain solution A;

[0140] Solution B: 162.5 g methylmagnesium chloride (3 M / L tetrahydrofuran solution);

[0141] Solution C: Mix 89 g of industrial concentrated hydrochloric acid and 650 g of water to obtain Solution C.

[0142] The module parameters are set as follows:

[0143] Precooling module 1 has a temperature control of -5 to 5°C and a module volume of 50 mL;

[0144] Precooling module 2 temperature control -10 ~ 0 ℃, module volume 10mL

[0145] The temperature of the mixed reaction module is controlled at 0-10°C, and the module volume is 1.5L;

[0146] The temperature of the quenching module is controlled at 0-40°C, and the module volume is 350mL.

[0147] The specific operations are as follows:

[0148] The automatic feeding system was turned on, and solution A and solution B were fed by metering pumps 1 and 2, respectively. The flow rate of solution A was 49.7 mL / min, and the flow rate of solution B was 10 mL / min. After the two streams were precooled for 1 min by precooling modules 1 and 2, the materials entered the mixed reaction module. After staying for 25 min, the materials entered the quenching module; then metering pump 3 was turned on to continuously deliver dilute hydrochloric acid for quenching reaction (flow rate = 45.3 mL / min), and quenching was performed for 3.3 min. The system after the quenching reaction was post-processed: reduced pressure concentration, alkali adjustment, centrifugation, and recrystallization to obtain the target product 1-(1,10-phenanthroline-2-yl) ethyl ketone 32.4 g, HPLC purity 60%, yield 60%.

[0149] Method 2:

[0150] Solution A: 50 g of 1,10-phenanthroline-2-carbonitrile and 675 g of tetrahydrofuran were mixed to obtain solution A;

[0151] Solution B: 182.5 g methylmagnesium iodide (3 M / L tetrahydrofuran solution);

[0152] Solution C: Mix 89 g of industrial concentrated hydrochloric acid and 650 g of water to obtain Solution C.

[0153] The module parameters are set as follows:

[0154] Precooling module 1 has a temperature control of -5 to 5°C and a module volume of 55 mL;

[0155] Precooling module 2 temperature control -10 ~ 0 ℃, module volume 10mL

[0156] The temperature of the mixed reaction module is controlled at 0-10°C, and the module volume is 1.5L;

[0157] The temperature of the quenching module is controlled at 0-40°C, and the module volume is 500mL.

[0158] The specific operations are as follows:

[0159] The automatic feeding system was turned on, and solution A and solution B were fed by metering pumps 1 and 2, respectively. The flow rate of solution A was 55 mL / min, and the flow rate of solution B was 10 mL / min. After the two streams were precooled for 1 min by precooling modules 1 and 2, the materials entered the mixed reaction module. After staying for 23 min, the materials entered the quenching module; then metering pump 3 was turned on to continuously deliver dilute hydrochloric acid for quenching reaction (flow rate = 50 mL / min), and the quenching was 4.3 min. The system after the quenching reaction was post-processed: reduced pressure concentration, alkali adjustment, centrifugation, and recrystallization to obtain the target product 1-(1,10-phenanthroline-2-yl) ethyl ketone 37.9 g, HPLC purity 45%, yield 70%.

[0160] Method 3:

[0161] Solution A: 50 g of 1,10-phenanthroline-2-carbonitrile and 675 g of tetrahydrofuran were mixed to obtain solution A;

[0162] Solution B: 147.7 g methylmagnesium bromide (3M / L tetrahydrofuran solution);

[0163] Solution C: Mix 89 g of industrial concentrated hydrochloric acid and 650 g of water to obtain Solution C.

[0164] The module parameters are set as follows:

[0165] Precooling module 1 has a temperature control of -5 to 5°C and a module volume of 55 mL;

[0166] Precooling module 2 temperature control -10 ~ 0 ℃, module volume 10mL

[0167] The temperature of the mixed reaction module is controlled at 0-10°C, and the module volume is 1.5L;

[0168] The temperature of the quenching module is controlled at 0-40°C, and the module volume is 500mL.

[0169] The specific operations are as follows:

[0170] The automatic feeding system was turned on, and solution A and solution B were fed by metering pumps 1 and 2, respectively. The flow rate of solution A was 56 mL / min, and the flow rate of solution B was 10 mL / min. After the two streams were precooled for 1 min by precooling modules 1 and 2, the materials entered the mixed reaction module. After staying for 22.7 min, the materials entered the quenching module; then metering pump 3 was turned on to continuously deliver dilute hydrochloric acid for quenching reaction (flow rate = 50.8 mL / min), and quenching was performed for 4.3 min. The system after the quenching reaction was post-processed: reduced pressure concentration, alkali adjustment, centrifugation, and recrystallization to obtain 32.4 g of the target product 1-(1,10-phenanthroline-2-yl)ethanone, with an HPLC purity of 60% and a yield of 60%.

[0171] Method 4:

[0172] Solution A: 50 g of 1,10-phenanthroline-2-carbonitrile and 675 g of dichloromethane were mixed to obtain solution A;

[0173] Solution B: 162.5 g methylmagnesium chloride (3 M / L tetrahydrofuran solution);

[0174] Solution C: Mix 89 g of industrial concentrated hydrochloric acid and 650 g of water to obtain Solution C.

[0175] The module parameters are set as follows:

[0176] Precooling module 1 has a temperature control of -5 to 5°C and a module volume of 50 mL;

[0177] Precooling module 2 temperature control -10 ~ 0 ℃, module volume 10mL

[0178] The temperature of the mixed reaction module is controlled at 0-10°C, and the module volume is 1.5L;

[0179] The temperature of the quenching module is controlled at 0-40°C, and the module volume is 350mL.

[0180] The specific operations are as follows:

[0181] The automatic feeding system was turned on, and solution A and solution B were fed by metering pumps 1 and 2, respectively. The flow rate of solution A was 49.7 mL / min, and the flow rate of solution B was 10 mL / min. After the two streams were precooled for 1 min by precooling modules 1 and 2, the materials entered the mixed reaction module. After staying for 25 min, the materials entered the quenching module; then metering pump 3 was turned on to continuously deliver dilute hydrochloric acid for quenching reaction (flow rate = 45.3 mL / min), and quenching was performed for 3.3 min. The system after the quenching reaction was post-processed: reduced pressure concentration, alkali adjustment, centrifugation, and recrystallization to obtain the target product 1-(1,10-phenanthroline-2-yl) ethyl ketone 32.4 g, HPLC purity 64%, yield 60%.

[0182] Method 5:

[0183] Solution A: 50 g of 1,10-phenanthroline-2-carbonitrile and 675 g of tetrahydrofuran were mixed to obtain solution A;

[0184] Solution B: 218.6 g methylmagnesium chloride (3M / L tetrahydrofuran solution);

[0185] Solution C: Mix 89 g of industrial concentrated hydrochloric acid and 650 g of water to obtain Solution C.

[0186] The module parameters are set as follows:

[0187] Precooling module 1 has a temperature control of -5 to 5°C and a module volume of 50 mL;

[0188] Precooling module 2 has a temperature control range of -10 to 0°C and a module volume of 10 mL;

[0189] The temperature of the mixed reaction module is controlled at 0-10°C, and the module volume is 1.5L;

[0190] The temperature of the quenching module is controlled at 0-40°C, and the module volume is 350mL.

[0191] The specific operations are as follows:

[0192] The automatic feeding system was turned on, and solution A and solution B were fed by metering pumps 1 and 2, respectively. The flow rate of solution A was 49.7 mL / min, and the flow rate of solution B was 13.5 mL / min. After the two streams were precooled for 1 min by precooling modules 1 and 2, the materials entered the mixed reaction module, stayed for 23.7 min, and then entered the quenching module; then metering pump 3 was turned on to continuously deliver dilute hydrochloric acid for quenching reaction (flow rate = 45.3 mL / min), and quenching was performed for 3.2 min. The system after the quenching reaction was post-processed: reduced pressure concentration, alkali adjustment, centrifugation, and recrystallization to obtain the target product 1-(1,10-phenanthroline-2-yl) ethyl ketone 35.2 g, HPLC purity 70%, yield 65%.

[0193] Method 6:

[0194] Solution A: 50 g of 1,10-phenanthroline-2-carbonitrile and 675 g of tetrahydrofuran were mixed to obtain solution A;

[0195] Solution B: 162.5 g methylmagnesium chloride (3 M / L tetrahydrofuran solution);

[0196] Solution C: Mix 89 g of industrial concentrated hydrochloric acid and 650 g of water to obtain Solution C.

[0197] The module parameters are set as follows:

[0198] Precooling module 1 has a temperature control of -5 to 5°C and a module volume of 50 mL;

[0199] Precooling module 2 temperature control -10 ~ 0 ℃, module volume 10mL

[0200] The temperature of the mixed reaction module is controlled at 0-10°C, and the module volume is 2L;

[0201] The temperature of the quenching module is controlled at 0-40°C, and the module volume is 350mL.

[0202] The specific operations are as follows:

[0203] The automatic feeding system was turned on, and solution A and solution B were fed by metering pumps 1 and 2, respectively. The flow rate of solution A = 49.7 mL / min, and the flow rate of solution B = 10 mL / min. After the two streams were pre-cooled for 1 min by pre-cooling modules 1 and 2, the materials entered the mixed reaction module. After staying for 33.5 min, the materials entered the quenching module; then metering pump 3 was turned on to continuously deliver dilute hydrochloric acid for quenching reaction (flow rate = 45.3 mL / min), and quenching was performed for 3.3 min. The system after the quenching reaction was post-processed: reduced pressure concentration, alkali adjustment, centrifugation, and recrystallization to obtain 33.5 g of the target product 1-(1,10-phenanthroline-2-yl)ethanone, with an HPLC purity of 60% and a yield of 62%.

[0204] Method 7:

[0205] Solution A: 50 g of 1,10-phenanthroline-2-carbonitrile and 675 g of tetrahydrofuran were mixed to obtain solution A;

[0206] Solution B: 162.5 g methylmagnesium chloride (3 M / L tetrahydrofuran solution);

[0207] Solution C: Mix 89 g of industrial concentrated hydrochloric acid and 650 g of water to obtain Solution C.

[0208] The module parameters are set as follows:

[0209] Precooling module 1 has a temperature control of -5 to 5°C and a module volume of 50 mL;

[0210] Precooling module 2 temperature control -10 ~ 0 ℃, module volume 10mL

[0211] The temperature of the mixed reaction module is controlled at 0-10°C, and the module volume is 1L;

[0212] The temperature of the quenching module is controlled at 0-40°C, and the module volume is 350mL.

[0213] The specific operations are as follows:

[0214] The automatic feeding system was turned on, and solution A and solution B were fed by metering pumps 1 and 2, respectively. The flow rate of solution A was 49.7 mL / min, and the flow rate of solution B was 10 mL / min. After the two streams were precooled for 1 min by precooling modules 1 and 2, the materials entered the mixed reaction module, stayed for 16.7 min, and then entered the quenching module; then metering pump 3 was turned on to continuously deliver dilute hydrochloric acid for quenching reaction (flow rate = 45.3 mL / min), and quenching was performed for 3.3 min. The system after the quenching reaction was post-processed: reduced pressure concentration, alkali adjustment, centrifugation, and recrystallization to obtain the target product 1-(1,10-phenanthroline-2-yl) ethyl ketone 31.4 g, HPLC purity 60%, yield 58%.

[0215] Method 8 (expanded reaction):

[0216] Solution A: 3.5 kg of 1,10-phenanthroline-2-carbonitrile and 46.5 kg of tetrahydrofuran were mixed to obtain solution A;

[0217] Solution B: 11.4 kg methylmagnesium chloride (3 M / L tetrahydrofuran solution);

[0218] Solution C: Mix 5.2 kg of industrial concentrated hydrochloric acid and 65 kg of water to obtain Solution C.

[0219] The module parameters are set as follows:

[0220] The precooling module 1 has a temperature control range of -5 to 5°C and a module volume of 100 mL;

[0221] Precooling module 2 temperature control -10 ~ 0 ℃, module volume 20mL

[0222] The temperature of the mixed reaction module is controlled at 0-10°C, and the module volume is 3L;

[0223] The temperature of the quenching module is controlled at 0-40°C, and the module volume is 500mL.

[0224] The specific operations are as follows:

[0225] The automatic feeding system was turned on, and solution A and solution B were fed by metering pumps 1 and 2, respectively. The flow rate of solution A was 99.5 mL / min, and the flow rate of solution B was 21.5 mL / min. After the two streams were precooled for 1 min by precooling modules 1 and 2, the materials entered the mixed reaction module. After staying for 25 min, the materials entered the quenching module; then metering pump 3 was turned on to continuously deliver dilute hydrochloric acid for quenching reaction (flow rate = 125 mL / min), and quenching was performed for 2 min. The system after the quenching reaction was post-processed: standing for phase separation, taking the organic phase and concentrating under reduced pressure, crystallizing, and filtering to obtain 37.9 g of the target product 1-(1,10-phenanthroline-2-yl)ethanone, with an HPLC purity of 64% and a yield of 70%.

[0226] Comparative Example:

[0227] 1. The first step: Synthesis of 1,10-phenanthroline-1-oxide

[0228] Comparative Example 1:

[0229] Solution A: a mixed solution of 50 g of 1,10-phenanthroline monohydrate and 250 g of acetic acid, connected to metering pump 1;

[0230] Solution B: 41 g of 30% hydrogen peroxide connected to metering pump 2;

[0231] The specific parameters of the module are as follows:

[0232] Continuous flow reactor 1, circulation temperature reached 90 °C and reached stability, volume 510 mL;

[0233] The specific operations are as follows:

[0234] The automatic feeding system was turned on, and solution A and solution B were fed by metering pumps 1 and 2 respectively, with a flow rate of solution A = 7.5 ml / min and a flow rate of solution B = 1 ml / min; the two streams of materials entered the continuous flow reactor 1 and began to be slowly back-pressured to 0.1-0.2 MPa, and after staying for 60 minutes, they began to be collected in the concentration kettle; after the operation was completed, the reaction was concentrated under reduced pressure at P = 8 mmHg, T = 60°C to obtain 38.1 g of the target product 1,10-phenanthroline, 1-oxide, with an HPLC purity of 80% and a yield of 70%.

[0235] Comparative Example 2:

[0236] Solution A: a mixed solution of 50 g of 1,10-phenanthroline monohydrate and 250 g of acetic acid, connected to metering pump 1;

[0237] Solution B: 30% hydrogen peroxide 50g connected to metering pump 2;

[0238] The specific parameters of the module are as follows:

[0239] Continuous flow reactor 1, the circulation temperature reached 75 °C and reached stability, the volume was 420 mL;

[0240] The specific operations are as follows:

[0241] The automatic feeding system was turned on, and solution A and solution B were fed by metering pumps 1 and 2 respectively, with a flow rate of solution A = 6 ml / min and a flow rate of solution B = 1 ml / min; the two streams of materials entered the continuous flow reactor 1 and began to be slowly back-pressured to 0.1-0.2 MPa, and after staying for 60 minutes, they began to be collected in the concentration kettle; after the operation was completed, the reaction was concentrated under reduced pressure at P = 8 mmHg, T = 60°C to obtain 40 g of the target product 1,10-phenanthroline, 1-oxide, with an HPLC purity of 82% and a yield of 74%.

[0242] By comparing the various methods of the first step reaction in the above-mentioned comparative examples 1 and 2 with those in the embodiment, it can be seen that only under the flow rate ratio of the specific metering pump 1 and the metering pump 2 and the specific reaction temperature of the present invention, can a high-purity and high-yield 1,10-phenanthroline-1-oxide intermediate be obtained.

[0243] 2. Step 2 Synthesis of 1,10-phenanthroline-2-carbonitrile

[0244] Comparative Example 3:

[0245] Solution A': 16g potassium cyanide + 80g aqueous solution;

[0246] Solution B': 200 g dichloromethane;

[0247] Solution C': 16g 1,10-phenanthroline-1-oxide + 80g water + 10% (sodium hydroxide) solution, adjust the pH of the solution to alkaline;

[0248] Solution D': 11.5g benzoyl chloride + 25g dichloromethane solution;

[0249] The module parameters are set as follows:

[0250] Mixing module 1 temperature control 0 ~ 40 ℃, module volume: 20mL;

[0251] Mixing module 2 temperature control 0 ~ 40 ℃, module volume: 35mL;

[0252] The temperature of the mixed reaction module is controlled at 20-50°C, and the module volume is 200mL.

[0253] The specific operations are as follows:

[0254] The automatic feeding system was turned on, and solution A' and solution B' were fed by metering pumps respectively. The flow rate of solution A' was 3.6 mL / min, and the flow rate of solution B' was 6.4 mL / min. The two streams of materials passed through mixing module 1. After staying for 2 minutes, the materials entered mixing module 2 and metering pump 3 was turned on at the same time. The flow rate of solution C' was 5.4 mL / min. After staying for 2.3 minutes, the materials entered the mixed reaction module and metering pump 4 was turned on at the same time. The flow rate of solution D' was 1.3 mL / min. After staying for 12 minutes, the outflowing reaction liquid was post-treated: standing for phase separation and extraction and washing (until the cyanide test paper was negative); the organic phase was concentrated under reduced pressure, ethyl acetate was added for crystallization, and filtration was performed to obtain 8.3 g of the target product 1,10-phenanthroline-2-carbonitrile, with an HPLC purity of 67% and a yield of 50%.

[0255] Comparative Example 4:

[0256] Solution A': 16g sodium cyanide + 80g aqueous solution;

[0257] Solution B': 200 g dichloromethane;

[0258] Solution C': 16g 1,10-phenanthroline-1-oxide + 80g water + 10% (sodium hydroxide) solution, adjust the pH of the solution to alkaline;

[0259] Solution D': 11.5g benzoyl chloride + 25g dichloromethane solution;

[0260] The module parameters are set as follows:

[0261] Mixing module 1 temperature control 0 ~ 40 ℃, module volume: 20mL;

[0262] Mixing module 2 temperature control 0 ~ 40 ℃, module volume: 35mL;

[0263] The temperature of the mixed reaction module is controlled at 20-50°C, and the module volume is 150mL.

[0264] The specific operations are as follows:

[0265] The automatic feeding system was turned on, and solution A' and solution B' were fed by metering pumps respectively. The flow rate of solution A' was 3.6 mL / min, and the flow rate of solution B' was 6.4 mL / min. The two streams of materials passed through mixing module 1. After staying for 2 minutes, the materials entered mixing module 2 and metering pump 3 was turned on at the same time. The flow rate of solution C' was 5.4 mL / min. After staying for 2.3 minutes, the materials entered the mixed reaction module and metering pump 4 was turned on at the same time. The flow rate of solution D' was 1.3 mL / min. After staying for 9 minutes, the outflowing reaction liquid was post-treated: standing for phase separation and extraction and washing (until the cyanide test paper test was negative); the organic phase was concentrated under reduced pressure, ethyl acetate was added for crystallization, and filtration was performed to obtain 9.2 g of the target product 1,10-phenanthroline-2-carbonitrile, with an HPLC purity of 95% and a yield of 55%.

[0266] By comparing the methods of the second step reaction in the above-mentioned Comparative Examples 3 and 4 with those in the embodiments, it can be seen that only within the specific sodium cyanide raw material and the specific reaction time range of the present invention can a high-purity and high-yield 1,10-phenanthroline-2-carbonitrile intermediate be obtained.

[0267] 3. Step 3 Synthesis of 1-(1,10-phenanthroline-2-yl)ethanone

[0268] Comparative Example 5:

[0269] Solution A: 50 g of 1,10-phenanthroline-2-carbonitrile and 675 g of toluene were mixed to obtain solution A;

[0270] Solution B: 162.5 g methylmagnesium chloride (3 M / L tetrahydrofuran solution);

[0271] Solution C: Mix 89 g of industrial concentrated hydrochloric acid and 650 g of water to obtain Solution C.

[0272] The module parameters are set as follows:

[0273] Precooling module 1 has a temperature control of -5 to 5°C and a module volume of 50 mL;

[0274] Precooling module 2 temperature control -10 ~ 0 ℃, module volume 10mL

[0275] The temperature of the mixed reaction module is controlled at 0-10°C, and the module volume is 1.5L;

[0276] The temperature of the quenching module is controlled at 0-40°C, and the module volume is 350mL.

[0277] The specific operations are as follows:

[0278] The automatic feeding system was turned on, and solution A and solution B were fed by metering pumps 1 and 2, respectively. The flow rate of solution A was 49.7 mL / min, and the flow rate of solution B was 10 mL / min. After the two streams were precooled for 1 min by precooling modules 1 and 2, the materials entered the mixed reaction module. After staying for 25 min, the materials entered the quenching module; then metering pump 3 was turned on to continuously deliver dilute hydrochloric acid for quenching reaction (flow rate = 45.3 mL / min), and quenching was performed for 3.3 min. The system after the quenching reaction was post-processed: reduced pressure concentration, alkali adjustment, centrifugation, and recrystallization to obtain the target product 1-(1,10-phenanthroline-2-yl) ethyl ketone 24.3 g, HPLC purity 50%, yield 45%.

[0279] Comparative Example 6:

[0280] Solution A: 50 g of 1,10-phenanthroline-2-carbonitrile and 675 g of tetrahydrofuran were mixed to obtain solution A;

[0281] Solution B: 109.3 g methylmagnesium chloride (3 M / L tetrahydrofuran solution);

[0282] Solution C: Mix 89 g of industrial concentrated hydrochloric acid and 650 g of water to obtain Solution C.

[0283] The module parameters are set as follows:

[0284] Precooling module 1 has a temperature control of -5 to 5°C and a module volume of 50 mL;

[0285] Precooling module 2 temperature control -10 ~ 0 ℃, module volume 10mL

[0286] The temperature of the mixed reaction module is controlled at 0-10°C, and the module volume is 1.5L;

[0287] The temperature of the quenching module is controlled at 0-40°C, and the module volume is 350mL.

[0288] The specific operations are as follows:

[0289] The automatic feeding system was turned on, and solution A and solution B were fed by metering pumps 1 and 2, respectively. The flow rate of solution A was 49.7 mL / min, and the flow rate of solution B was 6.7 mL / min. After the two streams were precooled for 1 min by precooling modules 1 and 2, the materials entered the mixed reaction module. After staying for 26.5 min, the materials entered the quenching module; then metering pump 3 was turned on to continuously deliver dilute hydrochloric acid for quenching reaction (flow rate = 45.3 mL / min), and quenching was performed for 3.4 min. The system after the quenching reaction was post-processed: reduced pressure concentration, alkali adjustment, centrifugation, and recrystallization to obtain the target product 1-(1,10-phenanthroline-2-yl) ethyl ketone 21.6 g, HPLC purity 40%, yield 40%.

[0290] By comparing the above comparative examples 5 and 6 with the various methods of the third step reaction in the embodiment, it can be seen that only within the specific solvent and raw material flow rate ratio range of the present invention can high-purity and high-yield 1-(1,10-phenanthroline-2-yl)ethanone be obtained.

[0291] In summary, the present invention provides a method for synthesizing 1-(1,10-phenanthroline-2-yl)ethanone by continuous flow reaction, using 1,10-phenanthroline monohydrate as a raw material, and reacting under specific continuous flow control parameters under precisely controlled reaction conditions, with high reaction efficiency and yield, simple operation, environmental protection and safety, and a prospect for industrialized scale-up production.

Claims

1. A method for continuous flow synthesis of 1-(1,10-phenanthroline-2-yl)ethanone, characterized in that: The steps include: (1) Synthesis of 1,10-phenanthroline-1-oxide: 1,10-phenanthroline or its hydrate is dissolved in an organic solvent to obtain an organic solution A, and the organic solution A is introduced into a continuous flow reactor I through a metering pump 1 and an oxidant solution through a metering pump 2. The continuous flow reactor I is kept at 85-95°C for reaction to obtain 1,10-phenanthroline-1-oxide; the organic solvent is acetic acid, and the oxidant solution is an aqueous solution of hydrogen peroxide; 1,10-phenanthroline in the organic solution A is hydrated with acetic acid, and the oxidant solution is an aqueous solution of hydrogen peroxide. The concentration of 1,0-phenanthroline or its hydrate is 9-17%, the aqueous hydrogen peroxide solution is 30%-50% aqueous hydrogen peroxide solution, the flow rate ratio of metering pump 1 to metering pump 2 is (6-7)x:1, x=y / z, y is the ratio of the concentration of the aqueous hydrogen peroxide solution to 30%, and z is the ratio of the concentration of 1,10-phenanthroline or its hydrate in organic solution A to 16.67%; the reaction conditions are: back pressure 0.1-0.2MPa, reaction time 60min; (2) Synthesis of 1,10-phenanthroline-2-carbonitrile: 1,10-phenanthroline-1-oxide and alkali are added with water to prepare an alkaline aqueous solution B, and at the same time, a sodium cyanide aqueous solution is introduced into a mixing module m through a metering pump 3, and dichloromethane or dichloroethane is introduced into a mixing module m through a metering pump 4 to obtain a reaction solution 1 after mixing; the molar ratio of 1,10-phenanthroline-1-oxide, water, and alkali in the aqueous solution B is 1:5:(18-19), and the concentration of sodium cyanide in the sodium cyanide aqueous solution is 7.4-16.7%; The reaction solution 1 is passed into the mixing module n, and the aqueous solution B is passed into the mixing module n through the metering pump 5, and then mixed to obtain the reaction solution 2; The reaction solution 2 is introduced into the continuous flow reactor II, and at the same time, a dichloromethane or dichloroethane solution of an acyl chloride activator is introduced into the continuous flow reactor II through a metering pump 6 to react for at least 10 minutes to obtain 1,10-phenanthroline-2-carbonitrile; The flow rate ratio of the metering pump 3 and the metering pump 4 is 1:(1.5-2); the flow rate of the metering pump 5 is 1:(1.6-2.1) to the sum of the flow rates of the metering pumps 3 and 4; the flow rate of the metering pump 6 is 1:(11.5-12.0) to the sum of the flow rates of the metering pumps 3, 4 and 5; The mixing condition of the mixing module m is 0-40°C for 1-3 min, and the mixing condition of the mixing module n is 0-40°C for 1-3 min; the reaction condition is 20-50°C for 11-18 min; The acyl chloride activator is benzoyl chloride; the concentration of benzoyl chloride in the dichloromethane or dichloroethane solution of benzoyl chloride is 25-35%; (3) Synthesis of 1-(1,10-phenanthroline-2-yl)ethanone: 1,10-phenanthroline-2-carbonitrile is dissolved in tetrahydrofuran or dichloromethane to obtain an organic solution B, and the organic solution B is precooled by a metering pump 7 through a precooling module a and then introduced into a reactor III. At the same time, the organic solution of a Grignard reagent is precooled by a metering pump 8 through a precooling module b and then introduced into a reactor III for reaction to obtain a reaction solution. The flow rate ratio of the metering pump 7 to the metering pump 8 is (3.5-5.6):1; the concentration of 1,10-phenanthroline-2-carbonitrile in the organic solution B is 6.5-7.5%, and the organic solution of the Grignard reagent is a tetrahydrofuran solution of methylmagnesium chloride, methylmagnesium bromide or methylmagnesium iodide, and the concentration is 2.5-3.5 M / L; The reaction solution is passed into a continuous flow quenching reactor, and at the same time, a hydrochloric acid aqueous solution is passed into the continuous flow quenching reactor through a metering pump 9, and 1-(1,10-phenanthroline-2-yl)ethanone is obtained after quenching the reaction; The flow rate ratio of the metering pump 7 and the metering pump 9 is (0.7-1.3):1; The precooling temperature of the precooling module a is -5~5°C, and the precooling time is 0.5~1.5min; the cooling temperature of the precooling module b is -10~0°C, and the precooling time is 0.5~1.5min; The reaction conditions are: 0-10°C for 20-30 min; The quenching reaction condition is quenching at 0-40° C. for 2-3.5 min.

2. The method according to claim 1, characterized in that The flow rate of the metering pump 1 is 6 ml / min to 900 ml / min, and the flow rate of the metering pump 2 is 1 ml / min to 150 ml / min.

3. The method according to claim 1, characterized in that The alkali in step (2) is any one or more of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

4. The method according to claim 1, characterized in that In step (2), the flow rate of the metering pump 3 is 1 ml / min to 150 ml / min, the flow rate of the metering pump 4 is 1.7 ml / min to 200 ml / min, the flow rate of the metering pump 5 is 1.5 ml / min to 200 ml / min, and the flow rate of the metering pump 6 is 0.3 ml / min to 50 ml / min.

5. The method according to claim 1, characterized in that The hydrochloric acid aqueous solution in step (3) is a 2.5% hydrochloric acid aqueous solution.

6. The method according to claim 1, characterized in that In step (3), the flow rate of the metering pump 7 is 4 ml / min to 200 ml / min, the flow rate of the metering pump 8 is 1 ml / min to 100 ml / min, and the flow rate of the metering pump 9 is 4 ml / min to 200 ml / min.

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