Method for preparing halogenated 2-aminobenzophenone through continuous photochemical rearrangement

Abstract

The invention provides a method for preparing halogenated 2-aminobenzophenone through continuous photochemical rearrangement, and the halogenated 2-aminobenzophenone is obtained by performing photochemical Fries rearrangement on aromatic amide in a solvent. The method does not use a catalyst and strong acid, has the advantages of mild reaction conditions, environmental friendliness and less wastewater, and is suitable for industrial production. After the product is purified, the yield of the obtained product can reach more than 60%, and the purity is 99.5%.

Description

[0001] This application is a divisional application of the application with the application number "202110151382.8", the application date of "2021-02-03", and the invention name of "A method for preparing aromatic ketones by green continuous photochemical rearrangement". Technical Field

[0002] The present invention belongs to the technical field of pharmaceutical synthesis, and relates to a new method for synthesizing aromatic ketones, specifically to a method for continuously preparing halogenated 2-aminobenzophenone by photochemical rearrangement. Background Art

[0003] Aromatic ketone compounds, as important chemical products and intermediates, have extensive applications in the fields of medicine, pesticides, dyes, etc. For example, aminoaryl ketone compounds are important intermediates in medicinal chemistry, dyes, and pesticide chemistry. They not only usually have certain medicinal activities themselves, but can also be used as intermediates to synthesize a variety of compounds with medicinal activities. For example, the chemical structures of the non-steroidal anti-inflammatory drugs amfenac sodium (Formula 1) and bromfenac sodium (Formula 2) both contain amino and carbonyl (i.e., ketone compound) structures.

[0004]

[0005] The main synthesis methods of aromatic ketone compounds include Friedel-Crafts acylation (F-C acylation reaction) and oxidative dehydrogenation of aromatic alcohols. For example, o-hydroxyacetophenone, which is used as a raw material for synthesizing chalcone compounds, is currently mainly synthesized by the following methods:

[0006] Method 1: Using a complex salt of aluminum trichloride and sodium chloride as a catalyst, without using a solvent for high-temperature reaction, the yield of o-hydroxyacetophenone is less than 50%.

[0007] Method 2: Preparing o-hydroxyacetophenone by catalyzing the Fries rearrangement reaction with anhydrous aluminum trichloride, and the yield is generally about 55%.

[0008] However, both of the above two methods use aluminum trichloride, generating a large amount of wastewater and waste residues.

[0009] In addition, aromatic ketones can also be obtained by reacting aromatic acyl chlorides with aromatic compounds. For example, 2-amino-5-chloro-2'-fluoro-benzophenone, abbreviated as FAB, is an intermediate for preparing anti-anxiety drugs midazolam, flutazolam, and fludiazepam. In the prior art, FAB is prepared by condensing o-fluorobenzoyl chloride and p-chloroaniline as shown in (Formula 1-1), and the yield of the product is 50%.

[0010] This method uses excessive o-fluorobenzoyl chloride, zinc chloride, and sulfuric acid during the production process, generating a large amount of wastewater.

[0011]

[0012] Compared with traditional methods, photochemical reactions have the advantage of mild conditions. Chinese patent document CN110922315A (201911210303.5) discloses a method for preparing a lorlatinib intermediate compound. Using 4-fluoroacetanilide as a raw material, a visible light Fries rearrangement reaction is carried out under a visible light catalyst and visible light irradiation to obtain the intermediate 2-amino-5-fluorobenzophenone. An ether solvent, wherein the visible light irradiation uses an LED lamp, and the power of the LED lamp is 18 watts to 72 watts; the visible light catalyst is g-C 3 N 4 . However, this patent also requires the use of a photocatalyst, which increases the difficulty and cost of the treatment process.

[0013] Summary of the Invention

[0014] In order to solve the problems existing in the synthesis of aromatic ketones in the prior art, such as the use of strong acid catalysts, large pollution, high cost, low yield, etc., the present invention provides a method for green continuous photochemical rearrangement to prepare aromatic ketones.

[0015] In order to achieve the above object, the present invention adopts the following technical solutions:

[0016] A method for green continuous photochemical rearrangement to prepare aromatic ketones, a solvent in which an aromatic amide or aromatic ester is dissolved, and a photochemical rearrangement reaction is carried out in a continuous flow reactor; to obtain ortho-aromatic ketones and / or para-aromatic ketones;

[0017] The synthesis route is shown in formula (2-1):

[0018]

[0019] Among them, X can be nitrogen (N), oxygen (O);

[0020] R can be an aromatic group or an aliphatic hydrocarbon group;

[0021] R' can be a halogen, an aromatic group, an aliphatic hydrocarbon group;

[0022] R and R' can be the same or different.

[0023] Preferably, the number of carbon atoms of R is 1 to 100. Further preferably 1-15, and still further preferably 2-10.

[0024] Preferably, the halogen is fluorine, chlorine, bromine.

[0025] Further preferably, when R and R’ are aromatic hydrocarbon groups, they are independently selected from phenyl, pyridine, thiophene, furan, naphthalene, anthracene; or substituted phenyl, pyridine, thiophene, furan, naphthalene, anthracene, and the substituent is an alkyl, alkenyl or alkynyl group with 2 to 6 carbon atoms.

[0026] When R and R’ are aliphatic hydrocarbon groups, they are independently selected from alkyl, alkenyl or alkynyl groups with 2 to 15 carbon atoms. More preferably, the aliphatic hydrocarbon group is selected from methyl, ethyl, propyl, butyl, isopropyl.

[0027] In the present invention, the solution moves in a single pass or circulates continuously in multiple passes relative to the light source.

[0028] In the present invention, "continuous" is defined as the movement of the reaction solution through the photoreactor while being irradiated by the light source or simultaneously exposed to the light of the light source. This movement should only occur in one direction, that is, from the inlet to the outlet of the photoreactor. This movement can also be paused during part of the photoreaction time (the movement speed is zero). Therefore, during the photoreaction time, there must be movement in the above direction for a certain period of time.

[0029] To ensure a certain residence / reacting time, the reaction solution flowing out from the outlet can re-enter the photoreactor from the inlet for multiple-pass cyclic photooxidation reaction.

[0030] The photoreaction time (i.e., the residence time of the reaction solution) is the time from when the reaction solution enters the reactor to when the reaction solution starts to flow out of the reactor. When the reaction is a multiple-pass cyclic reaction, this time (the total residence time of the reaction solution) is the sum of multiple single-pass photoreactions. In the present invention, the photoreaction time can be 0.1 to 100 hours. Preferably, the reaction time is 15 to 20 hours.

[0031] Therefore, the term "continuous" as used herein means that the solution containing aromatic amide or aromatic ester continuously flows through the photoreactor.

[0032] "Continuous" as used herein also means that if the raw materials can be constantly provided, the converted compounds can be continuously produced.

[0033] Preferably, the light irradiation temperature is 20°C to 100°C, more preferably, the light irradiation temperature is 20°C to 30°C; further preferably 24 to 26°C.

[0034] Preferably, the mass ratio of aromatic amide or aromatic ester to the solvent is 1:3 to 200, and the solvent is concentrated and removed after the reaction. Further preferably 1:20 to 160. Further preferably 1:80 to 160.

[0035] Preferably, the solvent is a polar solvent or a non-polar solvent capable of dissolving aromatic amide or aromatic ester. Further preferably, the solvent is one or a mixture of several of methanol, ethanol, isopropanol, acetonitrile, acetone, methyl acetate, ethyl acetate, methyl formate, ethyl formate, isopropyl acetate, tetrahydrofuran, dioxane, chlorobenzene, toluene, n-hexane, cyclohexane, n-heptane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, formic acid, acetic acid, and water.

[0036] Further preferably, the solvent is acetonitrile, methanol, a mixed solvent of methanol and water with a volume ratio of 1:1, or a mixed solvent of methanol, ethyl acetate and water with a volume ratio of 8:1:1. Preferably, the solvent is one of acetonitrile and methanol.

[0037] Preferably, the power of the light source is 0.1W to 250KW, and the wavelength of the light source is 180nm to 800nm.

[0038] Preferably, the light source is 180nm, 190nm, 200nm, 210nm, 220nm, 230nm, 240nm, 250nm, 260nm, 270nm, 280nm, 290nm, 300nm, 310nm, 320nm, 330nm, 340nm, 360nm, 380nm, 400nm, 450nm, 500nm, or a combination of any two of the above wavelengths.

[0039] Further preferably, the wavelength of the light source is 200 - 300nm.

[0040] Further preferably, the light source is one or a combination of several of low-pressure mercury lamp, medium-pressure mercury lamp, high-pressure mercury lamp, tungsten halogen lamp, metal halide lamp, light-emitting diode (LED), and different-shaped arrays (LEDArray) composed of light-emitting diodes.

[0041] Further preferably, the power of the light source is 200 - 600W. Even more preferably, the light source is a 250W low-pressure mercury lamp with a wavelength of 254nm.

[0042] Preferably, after the reaction, the reaction solution is eluted and separated by a chromatography silica gel column, and the eluent is a mixed solution of petroleum ether / ethyl acetate with a volume ratio of 10 - 3:1.

[0043] The reaction product of the present invention can be further purified by chromatography, countercurrent extraction, simple distillation rectification, or a combination thereof.

[0044] One or more technical solutions are provided in the embodiments of the present application, and at least have the following technical effects or advantages:

[0045] The present invention obtains ortho-aryl ketones and para-aryl ketones through the continuous photochemical Fries rearrangement of aromatic amides or aromatic esters in a solvent. The method of the present invention does not use a catalyst, strong acid, has mild reaction conditions, and has the advantages of environmental friendliness, less wastewater, and low cost.

[0046] The synthesis reaction of the present invention can be carried out in an organic solvent or water, or a combined solvent of both. The solvent has a wide selectivity, has low requirements for reaction conditions, and is suitable for industrial production.

[0047] In the prior art, the catalysts used for preparing aryl ketones include traditional Lewis acid catalysts, proton acid catalysts, and solid acid catalysts, which generate a large amount of wastewater and waste residues. In addition, there are also chromium salts, permanganates, Pd-based catalysts, etc. These catalytic systems often require one or more relatively expensive metals and will generate a large amount of metal waste. Under certain reaction conditions of the present invention, the total yield of the obtained product can reach 80% and the purity can reach 99.5%. Moreover, the defects of using a catalyst in the prior art for preparing aryl ketones and the low yield of preparing aryl ketones by photochemical reaction are overcome, the production efficiency is improved, and the production cost is saved. Description of the Drawings

[0048] Figure 1 is the liquid phase spectrum of 2-hydroxyacetophenone.

[0049] Figure 2 is the nuclear magnetic resonance spectrum of 2-hydroxyacetophenone.

[0050] Figure 3 is the liquid phase spectrum of 4-hydroxyacetophenone.

[0051] Figure 4 is the nuclear magnetic resonance spectrum of 4-hydroxyacetophenone.

[0052] Figure 5 is the liquid phase spectrum of 2-aminobenzophenone.

[0053] Figure 6 is the nuclear magnetic resonance spectrum of 2-aminobenzophenone.

[0054] Figure 7 is the liquid phase spectrum of 4-aminobenzophenone.

[0055] Figure 8 is the nuclear magnetic resonance spectrum of 4-aminobenzophenone.

[0056] Figure 9 is the liquid phase spectrum of 2-amino-5-chloro-2'-fluorobenzophenone.

[0057] Figure 10 is the nuclear magnetic resonance spectrum of 2-amino-5-chloro-2'-fluorobenzophenone.

[0058] Figure 11 It is a schematic diagram of the photoreactor used in the embodiments of the present invention.

[0059] Reference numerals:

[0060] 1 - Reaction liquid outlet; 2 - Reaction liquid inlet; 3 - Light source; 4 - Light source cold trap; 5 - Cold trap medium inlet; 6 - Cold trap medium outlet; 7 - Jacket; 8 - Jacket medium inlet; 9 - Jacket medium outlet. The outer diameter D of the reactor is 15 cm, and the inner diameter d is 10 cm. Detailed implementation manners

[0061] The present invention is further defined in the following examples. It should be understood that although these examples indicate the preferred embodiments of the present invention, they are given by way of illustration only and do not limit the claims of the present invention.

[0062] The detection instruments and methods (detection conditions) adopted in the specific embodiments of the present invention are as follows:

[0063] Gas chromatography analysis: Agilent 7800 gas chromatograph, Agilent DB - 5 capillary chromatographic column.

[0064] Nuclear magnetic resonance spectrum: Bruker 400M nuclear magnetic resonance.

[0065] Liquid phase detection: Agilent 1220HPLC, Agilent XDB - C18 250×4.6 mm chromatographic column, detection wavelength 254 nm.

[0066] The photoreactor is self - made and has the structure of the continuous photoreactor described in Patent CN207493676U. The schematic diagram of its structure is shown in Figure 11 as shown. The photoreactors used in the embodiments and comparative examples of the present invention are coiled tube type; the material is quartz.

[0067] Example 1:

[0068] A method for continuously preparing 2 - hydroxyacetophenone and 4 - hydroxyacetophenone by photochemical rearrangement,

[0069] To a 250 mL flask, phenyl acetate (1.36 g, 10 mmol, 1.0 eq) and acetonitrile (200 mL) were successively added and stirred until dissolved to obtain a reaction solution. The reaction solution was continuously pumped into a photoreactor (10 mL / min) using a peristaltic pump, and continuously irradiated with a low-pressure mercury lamp (250 W, wavelength 254 nm) at a temperature of 25 °C for 18 h. Samples were taken for in-process control, and the raw material residue was <5% (HPLC, area%). The reaction solution was concentrated under reduced pressure to dryness and eluted and separated using a silica gel column for chromatography (petroleum ether: ethyl acetate, volume ratio 10 - 3:1) to obtain 2-hydroxyacetophenone as a pale yellow oily liquid (0.71 g, 52% yield), purity (99.65%); and a colorless oily liquid, 4-hydroxyacetophenone (0.29 g, 22% yield), purity colorless crystal (99.86%).

[0070] The reaction equation is as follows:

[0071]

[0072] Figure 1 It is the liquid chromatogram of 2-hydroxyacetophenone. The peak of 2-hydroxyacetophenone is at 18.405 min in the figure; Figure 2 It is the nuclear magnetic resonance spectrum of 2-hydroxyacetophenone, 1 H NMR (400 MHz, CDCl 3 ) δ: 12.25 (s, 1H), 7.71 (m, 1H), 7.44 (m, 1H), 6.96 (m, 1H), 6.89 (m, 1H), 2.6 (s, 3H); Figure 3 It is the liquid chromatogram of 4-hydroxyacetophenone. The peak of 4-hydroxyacetophenone is at 14.405 min in the figure; Figure 4 It is the nuclear magnetic resonance spectrum of 4-hydroxyacetophenone, 1 H NMR (400 MHz, CDCl 3 ) δ: 8.69 (s, 1H), 7.92 (d, 2H), 6.98 (d, 2H), 2.6 (s, 3H).

[0073] Example 2:

[0074] The synthetic route for the continuous photochemical rearrangement to prepare 2-hydroxypropiophenone and 4-hydroxypropiophenone is as shown in Equation (Equation 2 - 3):

[0075] Add phenyl propionate (1.5 g, 10 mmol, 1.0 eq) and methanol (200 mL) to a 250 mL flask in sequence, and stir until dissolved and clear. Continuously pump the reaction solution into the photoreactor using a peristaltic pump, and irradiate continuously with a low-pressure mercury lamp (250 W, wavelength 254 nm) at a temperature of 25 °C for 18 h. Take samples for in-process control, and the raw material residue is <5% (HPLC, area%). Concentrate the reaction solution under reduced pressure to dryness, and separate it by gradient elution using a silica gel column for chromatography (petroleum ether: ethyl acetate, 10 - 3:1) to obtain 2-hydroxypropiophenone as a pale yellow oily liquid (0.82 g, 55% yield), with a purity of 99.3%, and 4-hydroxypropiophenone as an off-white crystalline powder (0.31 g, 21% yield) with a purity of 98.7%.

[0076]

[0077] Example 3:

[0078] The synthetic route for the continuous photochemical rearrangement to prepare 2-aminoacetophenone and 4-aminoacetophenone is shown in Formula (Formula 2-4):

[0079] Add acetanilide (1.35 g, 10 mmol, 1.0 eq) and methanol (200 mL) to a 250 mL container in sequence, and stir until dissolved and clear. Continuously pump the reaction solution into the photoreactor using a peristaltic pump, and irradiate with a low-pressure mercury lamp (250 W, wavelength 254 nm) at a temperature of 25 °C for 18 h. Take samples for in-process control, and the raw material residue is <5% (HPLC, area%). Concentrate the reaction solution under reduced pressure to dryness, and separate it by gradient elution using a silica gel column for chromatography (petroleum ether: ethyl acetate, 10 - 3:1) to obtain 2-aminoacetophenone as a yellowish-brown liquid (0.63 g, 47% yield) with a purity of 99.1%, and 4-aminoacetophenone as yellow needle-shaped crystals (0.19 g, 14% yield) with a purity of 99.4%.

[0080]

[0081] Example 4:

[0082] The synthetic route for the continuous photochemical rearrangement to prepare 2-aminopropiophenone and 4-aminopropiophenone is shown in Formula (Formula 2-5):

[0083] To a 250 mL flask, propionanilide (1.49 g, 10 mmol, 1.0 eq) and methanol:water volume ratio = 1:1 (200 mL) were successively added and stirred until dissolved. The reaction solution was continuously pumped into a photoreactor using a peristaltic pump and continuously irradiated with a low-pressure mercury lamp (250 W, wavelength 254 nm) at a temperature of 25 °C for 18 h. Samples were taken for in-process control, and the raw material residue was <5% (HPLC, area%). The reaction solution was concentrated to dryness under reduced pressure and separated by gradient elution using a silica gel column for chromatography (petroleum ether:ethyl acetate 10 - 3:1) to obtain yellow needle-like 2-aminopropiophenone (0.61 g, 41% yield), purity 98.2%, and yellow crystalline 4-aminopropiophenone (0.15 g, 19% yield), purity 97.3%.

[0084]

[0085] Example 5:

[0086] The synthetic route for the continuous photochemical rearrangement to prepare 2-aminobenzophenone and 4-aminobenzophenone is shown in Formula (Formula 2-6):

[0087] To a 250 mL container, benzylaniline (1.97 g, 10 mmol, 1.0 eq) and acetonitrile (200 mL) were successively added and stirred until dissolved. The reaction solution was continuously pumped into a photoreactor using a peristaltic pump and continuously irradiated with a low-pressure mercury lamp (250 W, wavelength 254 nm) at a temperature of 25 °C for 18 h. Samples were taken for in-process control, and the raw material residue was <5% (HPLC, area%). The reaction solution was concentrated to dryness under reduced pressure and separated by gradient elution using a silica gel column for chromatography (petroleum ether:ethyl acetate, 10 - 3:1) to obtain yellow needle-like 2-aminobenzophenone (1.0 g, 51% yield), purity 98.96%; and yellow crystalline 4-aminobenzophenone (0.45 g, 23% yield), purity 95.27%.

[0088]

[0089] Figure 5 This is the liquid chromatogram of 2-aminobenzophenone. The peak of 2-aminobenzophenone is at 22.270 min; Figure 6 This is the nuclear magnetic resonance spectrum of 2-aminobenzophenone 1 H NMR(400MHz,CDCl 3 )δ:7.626(m,2H),7.49(m,1H),7.44(m,3H),7.262(m,1H)6.705(m,1H),6.576(m,1H),6.1(m,1H).

[0090] Figure 7It is the liquid chromatogram of 4-aminobenzophenone. The peak of 4-aminobenzophenone appears at 18.230 min; Figure 8 It is the nuclear magnetic resonance spectrum of 4-aminobenzophenone 1 H NMR(400MHz,CDCl 3 )δ:7.71(d,2H),7.7(m,2H),7.52(m,1H),7.447(m,2H),6.649(m,2H),4.25(s,2H).

[0091] Example 6:

[0092] The synthetic route for the preparation of 2-amino-5-chloro-2'-fluorobenzophenone by continuous photochemical rearrangement is shown in Formula (Formula 2-7):

[0093] Add N-(4-chlorophenyl)-2-fluorobenzamide (2.49 g, 10 mmol, 1.0 eq) and acetonitrile (200 mL) successively into a 250 mL container and stir until dissolved and clear. Continuously pump the reaction solution into the photochemical reactor using a peristaltic pump, and irradiate continuously with a low-pressure mercury lamp (250 W, wavelength 254 nm) at a temperature of 25 °C for 18 h. Take samples for in-process control, and the raw material residue is <5% (HPLC, area%). Concentrate the reaction solution under reduced pressure to dryness, and separate by gradient elution using a silica gel column for chromatography (petroleum ether: ethyl acetate, 10 - 3:1) to obtain yellow crystals of 2-amino-5-chloro-2'-fluorobenzophenone (1.52 g, 61% yield) with a purity of 99.81%.

[0094]

[0095] Figure 9 It is the liquid chromatogram of 2-amino-5-chloro-2'-fluorobenzophenone. The peak of 2-amino-5-chloro-2'-fluorobenzophenone appears at 22.291 min in the figure.

[0096] Figure 10 It is the nuclear magnetic resonance spectrum of 2-amino-5-chloro-2'-fluorobenzophenone. In the figure, 1 H NMR(400MHz,CDCl 3 )δ:7.48(m,1H),7.4(m,1H),7.27(m,1H),7.25(m,1H),7.22(m,1H),7.16(m,1H),6.66(m,1H),6.4(s,2H).

[0097] Comparative Example 1

[0098] Heitaro OBARA et al. (SHORT COMMUNICATIONS, Photochemical Fries Rearrangement of Phenylcinnamic Acid, 1967, 40(4)) dissolved 1.0 g of phenylcinnamic acid in benzene and irradiated it at room temperature (450 W high-pressure mercury lamp) for 20 hours. After rearrangement, 0.1 g of 2-hydroxy-chalcone and 0.02 g of 4-hydroxy-chalcone were obtained.

[0099]

[0100] It can be seen that the total yield of the products 2-hydroxy-chalcone and 4-hydroxy-chalcone obtained by this method is only 12%. The method for preparing aryl ketones provided by the present invention can greatly improve the yield.

[0101] Comparative Example 2: Using diethyl ether as the solvent

[0102] For the continuous photochemical rearrangement to prepare 2-hydroxyacetophenone and 4-hydroxyacetophenone, phenyl acetate (1.36 g, 10 mmol, 1.0 eq) and diethyl ether (200 mL) were successively added to a 250 mL flask, stirred until clear to obtain a reaction solution. The reaction solution was continuously pumped into a photoreactor (10 mL / min) using a peristaltic pump and continuously irradiated with a low-pressure mercury lamp (250 W, wavelength 254 nm) at a temperature of 25 °C for 18 h. Samples were taken for in-process control. 20% of the raw materials reacted. After continuing irradiation for 24 h, only 32% of the raw materials reacted.

[0103] Comparative Example 3: Batchwise photochemical preparation of 2-hydroxyacetophenone and 4-hydroxyacetophenone

[0104] For the batchwise photochemical rearrangement to prepare 2-hydroxyacetophenone and 4-hydroxyacetophenone, phenyl acetate (1.36 g, 10 mmol, 1.0 eq) and acetonitrile (200 mL) were successively added to a 250 mL flask, stirred until clear to obtain a reaction solution. In a quartz photoreactor, it was continuously irradiated with a low-pressure mercury lamp (250 W, wavelength 254 nm) at a temperature of 25 °C for 18 h. Samples were taken for in-process control. 37% of the raw materials remained (HPLC, area%). After continuing irradiation for 24 h, 8% of the raw materials still remained.

[0105] Comparative Example 4: Using white light LED as the light source

[0106] For the continuous photochemical rearrangement to prepare 2-hydroxyacetophenone and 4-hydroxyacetophenone, phenyl acetate (1.36 g, 10 mmol, 1.0 eq) and acetonitrile (200 mL) were successively added to a 250 mL flask, stirred until clear to obtain a reaction solution. The reaction solution was continuously pumped into a photoreactor (10 mL / min) using a peristaltic pump and continuously irradiated with white light LED at a temperature of 25 °C for 18 h. Samples were taken for in-process control, and it was found that the raw materials did not react.

[0107] Comparative Example 5: Using a sodium lamp as the light source

[0108] For the preparation of 2-amino-5-chloro-2'-fluorobenzophenone by continuous photochemical rearrangement, N-(4-chlorophenyl)-2-fluorobenzamide (2.49 g, 10 mmol, 1.0 eq) and acetonitrile (200 mL) were successively added to a 250 mL container and stirred until dissolved and clear. The reaction solution was continuously pumped into the photoreactor using a peristaltic pump and continuously irradiated with a sodium lamp (600 W, wavelength 589.3 nm) at a temperature of 25 °C for 18 h. Sampling and testing showed that the raw materials did not react.

[0109] It can be seen from the comparative experiments that both the solvent and the light source have important effects on the yield and selectivity of the photochemical continuous preparation of aromatic ketones in the present invention.

Claims

1. A method for preparing halogenated 2-aminobenzophenone by continuous photochemical rearrangement, characterized in that, the solvent in which the aromatic amide is dissolved undergoes a photochemical rearrangement reaction in a continuous flow reactor; halogenated 2-aminobenzophenone is obtained; The synthetic route is shown in the following formula: R′ and R″ are F or Cl respectively.

2. The method according to claim 1, characterized in that, the halogenated 2-aminobenzophenone is 2-amino-5-chloro-2'-fluorobenzophenone, the aromatic amide is N-(4-chlorophenyl)-2-fluorobenzamide, and the halogenated 2-aminobenzophenone is 2-amino-5-chloro-2'-fluorobenzophenone; The synthetic route is shown in formula (2-7):

3. The method according to claim 1 or 2, characterized in that, the reaction time is 0.1 to 100 hours; preferably, the reaction time is 15 to 20 hours.

4. The method according to claim 1 or 2, characterized in that, the reaction temperature is 20°C to 100°C, preferably, the reaction temperature is 20°C to 30°C; more preferably 24 to 26°C.

5. The method according to claim 1 or 2, characterized in that, the mass ratio of N-(4-chlorophenyl)-2-fluorobenzamide to the solvent is 1:3 to 200; preferably 1:20 to 160; more preferably 1:50 to 70.

6. The method according to any one of claims 1 to 5, characterized in that, the solvent is a polar solvent or a non-polar solvent capable of dissolving the aromatic amide; preferably, the solvent is one or a mixture of several of methanol, ethanol, isopropanol, acetonitrile, acetone, methyl acetate, ethyl acetate, methyl formate, ethyl formate, isopropyl acetate, tetrahydrofuran, dioxane, chlorobenzene, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, formic acid, acetic acid, water.

7. The method according to claim 6, characterized in that, the solvent is acetonitrile.

8. The method according to claim 1 or 2, characterized in that, the wavelength of the light source used in the photochemical rearrangement reaction is 180 nm to 800 nm; preferably, the light source wavelength is 200 to 300 nm; Preferably, the power of the light source used in the photochemical rearrangement reaction is 0.1 W to 250 KW, more preferably, the light source power is 200 to 600 W, and further preferably 200 to 300 W.

9. The method according to claim 8, characterized in that, the light source is one or a combination of several of a low-pressure mercury lamp, a medium-pressure mercury lamp, a high-pressure mercury lamp, a tungsten halogen lamp, a metal halide lamp. Preferably, the light source is a 250 W low-pressure mercury lamp with a wavelength of 254 nm.

10. The method according to claim 1, characterized in that, the reaction solution after the reaction is separated by elution using a chromatographic silica gel column, and the eluent is a petroleum ether / ethyl acetate mixed solution with a volume ratio of 10 to 3:1.

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