Method for preparing drug intermediate 1, 5-benzoxaza derivative under catalysis of acidic eutectic solvent

Abstract

The invention discloses a method for preparing a drug intermediate 1, 5-benzoxaza # imgabs0 # derivative through catalysis of an acidic deep eutectic solvent, and belongs to the field of preparation of medical intermediates. Substituted ortho-aminophenol, beta-cyclic diketone and substituted benzaldehyde are used as reaction raw materials; the 1, 5-benzoxonitrogen # imgabs 1 # derivative containing a fused polycyclic structure is prepared by taking an acidic eutectic solvent as a reaction solvent and a catalyst. In the reaction, the catalytic activity and the reaction selectivity of the acidic eutectic solvent are high, and the acidic eutectic solvent can be recycled for multiple times without any treatment, so that the utilization efficiency of the reaction raw materials is improved, and the production cost and the environmental pollution are reduced at the same time. In addition, the purification of the product 1, 5-benzoxonitrogen # imgabs2 # derivative does not need recrystallization operation, and industrial, large-scale, economic and environment-friendly production can be easily realized.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical intermediate preparation, and specifically relates to a method for preparing a pharmaceutical intermediate 1,5-benzoxazepine by catalysis using an acidic deep eutectic solvent. Derivative method. Background Art

[0002] 1,5-Benzoxizone Derivatives are an important class of fused heterocyclic compounds containing both nitrogen and oxygen heteroatoms. Such compounds are not only widely present in nature, but many of them also have physiological and pharmacological activities such as anticonvulsant, antitumor, antidepressant, antianxiety, antibacterial, sedative, and hypnotic, and have good medicinal value.

[0003] Although 1,5-benzoxazine Derivatives have broad research and application prospects, but there are relatively few reports on their synthesis methods. At present, the commonly used method is to use transition metal salts as catalysts to obtain 1,5-benzoxazine through the dehydrohalogenation coupling reaction of aromatic halides. Derivatives. However, this method often has disadvantages such as low product yield, serious environmental pollution, and harsh reaction conditions. In order to overcome the above disadvantages, in 2023, Wang Lanzhi and others from Hebei Normal University used magnetic nanoparticles loaded with p-toluenesulfonic acid as a catalyst and anhydrous ethanol as a reaction solvent. At room temperature, 37 fused 1,5-benzoxazine with structures not reported in the literature were prepared in one pot. The method has the advantages of mild reaction conditions, relatively green reaction process, and recyclable catalyst (series synthesis of fused polycyclic 1,5-benzoxazine catalyzed by magnetic nanoparticle-supported p-toluenesulfonic acid) Compounds [J], Organic Chemistry, 2023, 43(11): 3977-3988). However, the above method also has some shortcomings. For example, due to the low reaction temperature (room temperature) and heterogeneous catalysis, the reaction time is relatively long, often requiring more than 7 hours. In addition, although increasing the temperature helps to increase the reaction rate, too high a reaction temperature will also cause the structure of the catalyst to change, thereby reducing its catalytic activity. Finally, since the reaction solvent cannot be recycled at the same time as the catalyst, the catalyst needs to be washed and vacuum dried before recycling, and the utilization rate of the reaction raw materials and reaction solvent is low, and environmental pollution still exists.

[0004] Therefore, a more economical, environmentally friendly, simple and efficient method for preparing 1,5-benzoxazine containing a fused polycyclic structure is studied and developed. This new method for the preparation of derivatives has very important theoretical significance and application prospects.

[0005] A low eutectic solvent is composed of a hydrogen bond acceptor (HBA) (quaternary ammonium salt) and a hydrogen bond donor (HBD) (carboxylic acid, polyol, urea, etc.) or a quaternary ammonium salt and a metal salt substance (such as ChCl / MCl2). It is considered to be a new generation of ionic liquids or their substitutes. The preparation process of the low eutectic solvent is simple and the cost is low. In addition, it has the advantages of biodegradability, non-toxicity, and non-volatility. Therefore, the low eutectic solvent can be used as a catalyst and reaction solvent in organic synthesis. Based on this, the present invention aims to propose an acidic low eutectic solvent to replace the above-mentioned complex and expensive magnetic nano-loaded p-toluenesulfonic acid as a catalyst and reaction solvent, and replace o-aminophenol, β-cyclic diketone and substituted benzaldehyde as reaction raw materials to catalyze the preparation of 1,5-benzoxazepine containing a fused polycyclic structure. The invention relates to a system and method for preparing a derivative, so that the catalyst can be recycled and regenerated, thereby achieving efficient, economical, environmentally friendly and continuous preparation of the drug intermediate 1,5-benzoxazepine The purpose of the derivatives is that the present invention has very broad market potential and application prospects. Summary of the invention

[0006] To achieve the above object, the present invention provides a 1,5-benzoxazine having a fused polycyclic structure. A method for preparing a derivative, wherein the method efficiently prepares 1,5-benzoxazine derivatives by a series reaction between substituted o-aminophenol, β-cyclic diketone and substituted benzaldehyde Derivatives have the advantages of easy availability of reaction raw materials, simple operation, short reaction time, high product yield, recyclable and regenerable catalysts, and ease of large-scale industrial use.

[0007] The purpose of the present invention can be achieved through the following technical solutions:

[0008] Preparation of drug intermediate 1,5-benzoxazepine catalyzed by an acidic deep eutectic solvent The method of producing a derivative comprises the following steps:

[0009] Substituted o-aminophenol and β-cyclic diketone are used as reaction raw materials, heated to a certain temperature in an acidic low eutectic solvent, and kept warm to react until the substituted o-aminophenol disappears, and then substituted benzaldehyde is added and continued to be heated to a predetermined temperature, and kept warm to react until the aldehyde disappears, and the filter is filtered while hot, and the filter residue is washed with ethanol and then vacuum dried to obtain 1,5-benzoxazine containing a fused polycyclic structure. derivative;

[0010] The chemical reaction formula of the above reaction is:

[0011]

[0012] Wherein R1 is any one of hydrogen, chlorine, bromine and methyl, and R2 is any one of phenyl, p-chlorophenyl, p-bromophenyl, p-methylphenyl, p-methoxyphenyl and 2,4-dichlorophenyl.

[0013] Optionally, the acidic deep eutectic solvent is composed of choline chloride and p-toluenesulfonic acid, wherein the molar ratio of choline chloride to p-toluenesulfonic acid is 1:3.

[0014] Optionally, the acidic deep eutectic solvent is used in an amount in grams that is 8 to 12 times the molar amount of the substituted o-aminophenol in millimoles.

[0015] Optionally, the substituted o-aminophenol is selected from

[0016]

[0017] Any of .

[0018] Optionally, the substituted benzaldehyde is selected from

[0019]

[0020] Any of .

[0021] Optionally, the molar ratio of the substituted o-aminophenol, the β-cyclic diketone and the substituted benzaldehyde is 1:1:1.

[0022] Optionally, the β-cyclic diketone is 1,3-cyclopentanedione or 1,3-indandione.

[0023] Optionally, the specific operation process of the above preparation method is: adding a preset volume of an acidic deep eutectic solvent into a three-necked flask at room temperature, and then adding substituted o-aminophenol and β-cyclic diketone in sequence under magnetic stirring to form a reaction system;

[0024] Then proceed as follows: heat the reaction system to a preset temperature under magnetic stirring and keep warm until the reaction is complete → add substituted benzaldehyde and continue to heat to a preset temperature, keep warm until the reaction is complete → naturally cool to 40°C and filter under reduced pressure → wash the filter residue with ethanol and then vacuum dry to obtain 1,5-benzoxazine containing a fused polycyclic structure Derivatives → filtrate is directly recycled → filtrate that cannot be recycled is regenerated.

[0025] Optionally, the reaction system is heated to a preset temperature under magnetic stirring and kept warm until the reaction is complete: the reaction system is heated to 72-87° C. in a methyl silicone oil bath under magnetic stirring, and this temperature is maintained until the reaction is complete, with continuous stirring during the insulation process, and the insulation reaction time is 23-34 min;

[0026] Add substituted benzaldehyde and continue heating to the preset temperature, and keep warm until the reaction is complete: continue adding substituted benzaldehyde to the reaction system and heat to 78-85°C, maintain this temperature until the reaction is complete, continue stirring during the insulation process, and the insulation reaction time is 31-54 minutes;

[0027] When the temperature naturally drops to 40°C, vacuum filter: Immediately stop stirring and naturally cool to 40°C, vacuum filter to obtain filter residue and filtrate;

[0028] The filter residue was washed with ethanol and then dried in vacuum to obtain 1,5-benzoxazine containing a fused polycyclic structure. Derivatives: Wash the residue three times with ethanol and then vacuum dry at 85°C to constant weight to obtain 1,5-benzoxazine derivative;

[0029] The filtrate is directly recycled: the filtrate is directly added to the reaction raw materials without any treatment for the next round of reaction, and recycled for multiple times. The 1,5-benzoxazine obtained in each cycle The purity of the derivatives was monitored by high performance liquid chromatography and the yield was calculated. When the purity was lower than 98.5% or the yield decreased by more than 5%, the recycling was stopped.

[0030] The filtrate that cannot be recycled is regenerated by adding a preset volume of ethyl acetate to the filtrate that has stopped being recycled, heating under reflux for 30 minutes under magnetic stirring, stopping stirring, separating the liquid with a separatory funnel, and then adding the same volume of ethyl acetate to the lower layer of liquid, continuing to heat under reflux for 30 minutes under magnetic stirring, stopping stirring, separating the liquid with a separatory funnel, and performing this operation three times in total; the lower layer of liquid finally obtained is vacuum dried at 85°C for 8 hours to form a regenerated acidic low eutectic solvent.

[0031] Optionally, the volume usage of the ethyl acetate is 1 to 3 times the mass usage of the acidic low eutectic solvent.

[0032] Beneficial effects of the present invention:

[0033] The invention discloses an acidic deep eutectic solvent catalyzed preparation of drug intermediate 1,5-benzoxazepine The method for preparing a 1,5-benzoxazine derivative containing a fused polycyclic structure is carried out by using substituted o-aminophenol, β-cyclic diketone and substituted benzaldehyde as reaction raw materials and using an acidic deep eutectic solvent as a reaction solvent and catalyst. Derivatives. In the reaction, the acidic low eutectic solvent has high catalytic activity and reaction selectivity, and can be recycled many times without any treatment, which improves the utilization efficiency of the reaction raw materials while also reducing production costs and environmental pollution. In addition, the product 1,5-benzoxazine The purification of the derivatives does not require recrystallization operations, and industrial large-scale, economical and environmentally friendly production can be easily achieved. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] The present invention will be further described below in conjunction with the accompanying drawings.

[0035] Figure 1 Preparation of 1,5-benzoxazine containing fused polycyclic structure Process flow diagram of derivatives. DETAILED DESCRIPTION

[0036] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0037] The reaction product 1,5-benzoxazine in the following example The instruments used for the structural characterization of the derivatives are: the nuclear magnetic resonance hydrogen spectrum uses the AVANCE 400MHz nuclear magnetic resonance instrument of Bruker, Germany, the infrared spectrum uses the 6700 Fourier transform infrared spectrometer (KBr pellet) of Nicolet Instruments, USA, and the melting point uses the X-4 microscopic melting point determination instrument of Gongyi Kerui Instrument Co., Ltd.; the reaction product 1,5-benzoxazine The purity of the derivatives was characterized using a high performance liquid chromatograph (UFLC-2010PLUS) from Shimadzu Corporation of Japan.

[0038] The acidic low eutectic solvent used in the present invention is prepared by heating and stirring choline chloride and p-toluenesulfonic acid. The specific preparation process refers to the relevant literature: Research on the methyl esterification reaction of sunflower oil catalyzed by acidic low eutectic solvent [J], Journal of Henan University of Technology (Natural Science Edition), 2020, 41(6): 41-46.

[0039] like Figure 1 The present invention is a method for preparing 1,5-benzoxazine containing a fused polycyclic structure. Process flow diagram of derivatives.

[0040] Example 1

[0041] 10-phenyl-2,3,4,10-tetrahydro-1H-benzo[b]cyclopenta[e][1,4]oxazepine -1-Keto

[0042]

[0043] At room temperature, 1.0 mmol o-aminophenol and 1.0 mmol 1,3-cyclopentanedione were added to a 50 mL four-necked flask with a magnetic stirrer, a spherical condenser and a thermometer containing 8 g of an acidic low eutectic solvent (n (choline chloride): n (p-toluenesulfonic acid) = 1:3) in sequence, and then the mixture was heated uniformly in a methyl silicone oil bath to 72°C under stirring, and the temperature was kept warm for 23 min when the raw material point disappeared by TLC (thin plate chromatography). 1.0 mmol benzaldehyde was immediately added, and the mixture was heated to 83°C under stirring and the temperature was kept warm for 49 min when the raw material point disappeared by TLC (thin plate chromatography). Stirring was stopped immediately, and the mixture was naturally cooled to 40°C and filtered under reduced pressure to obtain a filtrate and a filter residue. The filtrate was directly added to the reaction raw material for recycling, and the filter residue after being naturally cooled to room temperature was washed three times with 3 ml of ethanol, and then vacuum dried at 85°C to constant weight to obtain 0.24 g of a yellow solid. The structure of the solid was determined to be 10-phenyl-2,3,4,10-tetrahydro-1H-benzo[b]cyclopenta[e][1,4]oxazepine by H NMR and IR analysis. -1-ketone; the purity was 99.2% as determined by high performance liquid chromatography, and finally 10-phenyl-2,3,4,10-tetrahydro-1H-benzo[b]cyclopenta[e][1,4]oxazepine was obtained by calculation. The yield of -1-ketone was 87%.

[0044] mp: 241~243℃; 1 H NMR (400MHz, DMSO-d6): δ10.24 (s, 1H), 7.11~7.26 (m, 5H), 6.91~6.95 (m, 1H), 6.68~6.74 (m, 1H), 6.61 (m, 1H), 6.16 (s, 1H), 2.77~2.87 (m, 2H), 2.32~2.40 (m, 2H)ppm; IR (KBr): ν3271, 1668, 1306cm -1 .

[0045] Example 2

[0046] 10-(4-Chlorophenyl)-2,3,4,10-tetrahydro-1H-benzo[b]cyclopenta[e][1,4]oxazepine -1-Keto

[0047]

[0048] At room temperature, first, 1.0 mmol o-aminophenol and 1.0 mmol 1,3-cyclopentanedione were added to a 50 mL four-necked flask with a magnetic stirrer, a spherical condenser and a thermometer containing 9 g of an acidic low eutectic solvent (n (choline chloride): n (p-toluenesulfonic acid) = 1:3) in sequence, and then the mixture was heated uniformly in a methyl silicone oil bath to 72°C under stirring, and the temperature was kept warm for 24 min when the raw material point disappeared by TLC (thin plate chromatography). 1.0 mmol p-chlorobenzaldehyde was immediately added, and the mixture was heated to 80°C under stirring and the temperature was kept warm for 43 min when the raw material point disappeared by TLC (thin plate chromatography). Stirring was immediately stopped, and the mixture was naturally cooled to 40°C and filtered under reduced pressure to obtain a filtrate and a filter residue. The filtrate was directly added to the reaction raw material for recycling, and the filter residue after being naturally cooled to room temperature was washed three times with 4 ml ethanol, and then vacuum dried at 85°C to constant weight to obtain 0.29 g of a yellow solid. The structure of the solid was determined to be 10-(4-chlorophenyl)-2,3,4,10-tetrahydro-1H-benzo[b]cyclopenta[e][1,4]oxazepine by H NMR and IR analysis. -1-ketone; the purity was 99.4% as determined by high performance liquid chromatography, and finally 10-(4-chlorophenyl)-2,3,4,10-tetrahydro-1H-benzo[b]cyclopenta[e][1,4]oxazepine was obtained by calculation. The yield of -1-ketone was 91%.

[0049] mp: 242~244℃; 1 H NMR (400MHz, DMSO-d6): δ10.07(s, 1H), 7.23~7.27(m, 2H), 7.10~7.13(m, 2H), 7.06~7.08(m, 1H), 6.88~6.93(m, 1H), 6.7 4~6.79 (m, 1H), 6.61~6.63 (m, 1H), 6.14 (s, 1H), 2.79~2.85 (m, 2H), 2.41~2.43 (m, 2H)ppm; IR (KBr): ν3389, 1650, 1207cm -1 .

[0050] Example 3

[0051] 7-Methyl-10-phenyl-2,3,4,10-tetrahydro-1H-benzo[b]cyclopenta[e][1,4]oxazepine -1-Keto

[0052]

[0053] At room temperature, first, 1.0mmol 2-amino-5-methylphenol and 1.0mmol 1,3-cyclopentanedione were added to a 50mL four-necked flask with a magnetic stirrer, a spherical condenser and a thermometer containing 9g of an acidic low eutectic solvent (n(choline chloride):n(p-toluenesulfonic acid)=1:3) in sequence, and then the mixture was heated uniformly in a methyl silicone oil bath to 82°C under stirring, and the temperature was monitored by TLC (thin plate chromatography). When the raw material point disappeared, the heat preservation reaction time was 30min. 1.0mmol benzaldehyde was immediately added, and the mixture was heated to 83°C under stirring. The temperature was monitored by TLC (thin plate chromatography). When the raw material point disappeared, the heat preservation reaction time was 46min. Stirring was immediately stopped, and the mixture was naturally cooled to 40°C and filtered under reduced pressure to obtain a filtrate and a filter residue. The filtrate was directly added to the reaction raw material for recycling, and the filter residue after being naturally cooled to room temperature was washed three times with 5ml ethanol, and then vacuum dried at 85°C to constant weight to obtain 0.26g of a white solid. The structure of the solid was determined to be 7-methyl-10-phenyl-2,3,4,10-tetrahydro-1H-benzo[b]cyclopenta[e][1,4]oxazepine by H NMR and IR analysis. -1-ketone; the purity was 99.4% as determined by high performance liquid chromatography, and finally 7-methyl-10-phenyl-2,3,4,10-tetrahydro-1H-benzo[b]cyclopenta[e][1,4]oxazepine was obtained by calculation. The yield of -1-ketone was 89%.

[0054] mp: 215~217℃; 1 H NMR (400MHz, DMSO-d6): δ10.37 (s, 1H), 7.21~7.25 (m, 2H), 7.13~7.18 (m, 3H), 6.85~6.87 (m, 1H), 6.63~6.6 5 (m, 2H), 6.26 (s, 1H), 2.73~2.85 (m, 2H), 2.32~2.37 (m, 2H), 2.08 (s, 3H)ppm; IR (KBr): ν3308, 1626, 1186cm -1 .

[0055] Example 4

[0056] 7-Methyl-10-(4-chlorophenyl)-2,3,4,10-tetrahydro-1H-benzo[b]cyclopenta[e][1,4]oxazepine -1-Keto

[0057]

[0058] At room temperature, first, 1.0 mmol 2-amino-5-methylphenol and 1.0 mmol 1,3-cyclopentanedione were added to a 50 mL four-necked flask with a magnetic stirrer, a spherical condenser and a thermometer containing 10 g of an acidic low eutectic solvent (n (choline chloride): n (p-toluenesulfonic acid) = 1:3) in sequence, and then heated in a methyl silicone oil bath to 82°C under stirring, and monitored by TLC (thin plate chromatography). When the raw material point disappears, the heat preservation reaction time is 32 min. Immediately add 1.0 mmol p-chlorobenzaldehyde, continue stirring and heating to 82°C, and monitor by TLC (thin plate chromatography). When the raw material point disappears, the heat preservation reaction time is 51 min. Immediately stop stirring, cool naturally to 40°C, and filter under reduced pressure to obtain a filtrate and a filter residue. The filtrate was directly added to the reaction raw materials for recycling, and the filter residue after natural cooling to room temperature was washed three times with 5 ml of ethanol, and then vacuum dried at 85°C to constant weight to obtain 0.30 g of light yellow solid. The structure of the solid was determined by nuclear magnetic resonance hydrogen spectrum and infrared spectrum analysis to be 7-methyl-10-(4-chlorophenyl)-2,3,4,10-tetrahydro-1H-benzo[b]cyclopenta[e][1,4]oxazepine -1-ketone; the purity was 99.2% as determined by high performance liquid chromatography, and finally 7-methyl-10-(4-chlorophenyl)-2,3,4,10-tetrahydro-1H-benzo[b]cyclopenta[e][1,4]oxazepine was obtained by calculation. The yield of -1-ketone was 91%.

[0059] mp: 259~261℃; 1 H NMR (400MHz, DMSO-d6): δ10.30 (s, 1H), 8.01~8.05 (m, 2H), 7.44~7.47 (m, 2H), 6.91~6.94 (m, 1H), 6.73 (s, 1H), 6.6 9~6.72 (m, 1H), 6.25 (s, 1H), 2.76~2.87 (m, 2H), 2.32~2.39 (m, 2H), 2.06 (s, 3H)ppm; IR (KBr): ν3317, 1659, 1189cm -1 .

[0060] Example 5

[0061] 11-phenyl-5,11-dihydro-12H-benzo[b]indeno[1,2-e][1,4]oxazepine -12-Keto

[0062]

[0063] At room temperature, 1.0 mmol o-aminophenol and 1.0 mmol 1,3-indandione were added to a 50 mL four-necked flask with a magnetic stirrer, a spherical condenser and a thermometer containing 9 g of an acidic low eutectic solvent (n (choline chloride): n (p-toluenesulfonic acid) = 1:3) in sequence, and then the mixture was heated uniformly in a methyl silicone oil bath to 79°C under stirring, and the temperature was kept warm for 28 min when the raw material point disappeared by TLC (thin plate chromatography). 1.0 mmol benzaldehyde was immediately added, and the mixture was heated to 82°C under stirring and the temperature was kept warm for 43 min when the raw material point disappeared by TLC (thin plate chromatography). Stirring was immediately stopped and the mixture was naturally cooled to 40°C and filtered under reduced pressure to obtain a filtrate and a filter residue. The filtrate was directly added to the reaction raw material for recycling, and the filter residue after being naturally cooled to room temperature was washed three times with 4 ml ethanol, and then vacuum dried at 85°C to constant weight to obtain 0.30 g of a yellow solid. The structure of the solid was determined to be 11-phenyl-5,11-dihydro-12H-benzo[b]indeno[1,2-e][1,4]oxazepine by H NMR and IR analysis. -12-ketone; the purity was 99.5% as determined by high performance liquid chromatography, and finally 11-phenyl-5,11-dihydro-12H-benzo[b]indeno[1,2-e][1,4]oxazepine was obtained by calculation. The yield of -12-ketone was 93%.

[0064] mp: 206~208℃; 1 H NMR (400MHz, DMSO-d6): δ10.24 (s, 1H), 7.35~8.00 (m, 4H), 7.19~7.25 (m, 5H), 6.67~7.52 (m, 4H), 6.37 (s, 1H)ppm; IR (KBr): ν3311, 1673, 1618, 1574cm -1 .

[0065] Example 6

[0066] 11-(4-Methylphenyl)-5,11-dihydro-12H-benzo[b]indeno[1,2-e][1,4]oxazepine -12-Keto

[0067]

[0068] At room temperature, 1.0 mmol o-aminophenol and 1.0 mmol 1,3-indandione were added to a 50 mL four-necked flask with a magnetic stirrer, a spherical condenser and a thermometer containing 11 g of an acidic low eutectic solvent (n (choline chloride): n (p-toluenesulfonic acid) = 1:3) in sequence, and then the mixture was heated uniformly in a methyl silicone oil bath to 80°C under stirring, and the temperature was monitored by TLC (thin plate chromatography). When the raw material point disappeared, the heat preservation reaction time was 27 min. 1.0 mmol p-methylbenzaldehyde was immediately added, and the mixture was heated to 84°C under stirring. The temperature was monitored by TLC (thin plate chromatography). When the raw material point disappeared, the heat preservation reaction time was 45 min. Stirring was immediately stopped, and the mixture was naturally cooled to 40°C and filtered under reduced pressure to obtain a filtrate and a filter residue. The filtrate was directly added to the reaction raw material for recycling, and the filter residue after being naturally cooled to room temperature was washed three times with 5 ml of ethanol, and then vacuum dried at 85°C to constant weight to obtain 0.31 g of a yellow solid. The structure of the solid was determined to be 11-(4-methylphenyl)-5,11-dihydro-12H-benzo[b]indeno[1,2-e][1,4]oxazepine by H NMR and IR analysis. -12-ketone; the purity was 99.5% as determined by high performance liquid chromatography, and finally 11-(4-methylphenyl)-5,11-dihydro-12H-benzo[b]indeno[1,2-e][1,4]oxazepine was obtained by calculation. The yield of -12-ketone was 91%.

[0069] mp: 225~227℃; 1 H NMR (400MHz, DMSO-d6): δ10.22 (s, 1H), 7.41~8.06 (m, 4H), 6.94~7.52 (m, 4H), 6.7 2~7.13 (m, 4H), 6.34 (s, 1H), 2.12 (s, 3H)ppm; IR (KBr): ν3301, 1676, 1604, 1579cm -1 .

[0070] Example 7

[0071] 8-Chloro-11-phenyl-5,11-dihydro-12H-benzo[b]indeno[1,2-e][1,4]oxazepine -12-Keto

[0072]

[0073] At room temperature, first, 10g of acidic low eutectic solvent (n (choline chloride): n (p-toluenesulfonic acid) = 1:3) was added to a 50mL four-necked flask with a magnetic stirrer, a spherical condenser and a thermometer, and then 1.0mmol 2-amino-5-chlorophenol and 1.0mmol 1,3-indandione were added in sequence, and then the mixture was heated uniformly in a methyl silicone oil bath to 85°C under stirring, and the temperature was monitored by TLC (thin plate chromatography). When the raw material point disappeared, the heat preservation reaction time was 32min. 1.0mmol benzaldehyde was immediately added, and the mixture was heated to 83°C under stirring. The temperature was monitored by TLC (thin plate chromatography). When the raw material point disappeared, the heat preservation reaction time was 52min. Stirring was immediately stopped, and the mixture was naturally cooled to 40°C and filtered under reduced pressure to obtain a filtrate and a filter residue. The filtrate was directly added to the reaction raw material for recycling, and the filter residue after being naturally cooled to room temperature was washed three times with 4ml ethanol, and then vacuum dried at 85°C to constant weight to obtain 0.32g of a yellow solid. The structure of the solid was determined to be 8-chloro-11-phenyl-5,11-dihydro-12H-benzo[b]indeno[1,2-e][1,4]oxazepine by H NMR and IR analysis. -12-ketone; the purity was 99.2% as determined by high performance liquid chromatography, and finally 8-chloro-11-phenyl-5,11-dihydro-12H-benzo[b]indeno[1,2-e][1,4]oxazepine was obtained by calculation. The yield of -12-ketone was 88%.

[0074] mp: 238~240℃; 1 H NMR (400MHz, DMSO-d6): δ10.28 (s, 1H), 7.40~7.96 (m, 4H), 7.20~7.28 (m, 5H), 6.66~7.50 (m, 3H), 6.36 (s, 1H)ppm; IR (KBr): ν3292, 1669, 1599, 1577cm -1 .

[0075] Example 8

[0076] 8-Methyl-11-(4-chlorophenyl)-5,11-dihydro-12H-benzo[b]indeno[1,2-e][1,4]oxazepine -12-Keto

[0077]

[0078] At room temperature, first, 10g of acidic low eutectic solvent (n (choline chloride): n (p-toluenesulfonic acid) = 1:3) was added to a 50mL four-necked flask with a magnetic stirrer, a spherical condenser and a thermometer, and then 1.0mmol 2-amino-5-methylphenol and 1.0mmol 1,3-indandione were added in sequence, and then the mixture was heated uniformly to 85°C in a methyl silicone oil bath under stirring, and the temperature was monitored by TLC (thin plate chromatography). When the raw material point disappeared, the heat preservation reaction time was 35min. 1.0mmol benzaldehyde was immediately added, and the mixture was heated to 78°C with continued stirring. The temperature was monitored by TLC (thin plate chromatography). When the raw material point disappeared, the heat preservation reaction time was 31min. Stirring was immediately stopped, and the mixture was naturally cooled to 40°C and filtered under reduced pressure to obtain a filtrate and a filter residue. The filtrate was directly added to the reaction raw material for recycling, and the filter residue after being naturally cooled to room temperature was washed three times with 5ml ethanol, and then vacuum dried at 85°C to constant weight to obtain 0.35g of a yellow solid. The structure of the solid was determined to be 8-methyl-11-(4-chlorophenyl)-5,11-dihydro-12H-benzo[b]indeno[1,2-e][1,4]oxazepine by H NMR and IR analysis. -12-ketone; the purity was 99.5% as determined by high performance liquid chromatography, and finally 8-methyl-11-(4-chlorophenyl)-5,11-dihydro-12H-benzo[b]indeno[1,2-e][1,4]oxazepine was obtained by calculation. The yield of -12-ketone was 94%.

[0079] mp: 231~233℃; 1 H NMR (400MHz, DMSO-d6): δ10.22 (s, 1H), 7.34~7.98 (m, 4H), 7.16~7.29 (m, 4H), 6.5 1~7.17 (m, 3H), 6.28 (s, 1H), 2.19 (s, 3H)ppm; IR (KBr): ν3314, 1673, 1619, 1585cm -1 .

[0080] Example 9

[0081] 8-Chloro-11-(4-methoxyphenyl)-5,11-dihydro-12H-benzo[b]indeno[1,2-e][1,4]oxazepine -12-Keto

[0082]

[0083] At room temperature, first, 1.0 mmol 2-amino-5-chlorophenol and 1.0 mmol 1,3-indandione were added to a 50 mL four-necked flask with a magnetic stirrer, a spherical condenser and a thermometer containing 12 g of an acidic low eutectic solvent (n (choline chloride): n (p-toluenesulfonic acid) = 1:3) in sequence, and then heated in a methyl silicone oil bath to 87°C under stirring, and monitored by TLC (thin plate chromatography). When the raw material point disappears, the heat preservation reaction time is 34 min. Immediately add 1.0 mmol p-methoxybenzaldehyde, continue stirring and heating to 85°C, and monitor by TLC (thin plate chromatography). When the raw material point disappears, the heat preservation reaction time is 31 min. Immediately stop stirring, cool naturally to 40°C, and filter under reduced pressure to obtain a filtrate and a filter residue. The filtrate was directly added to the reaction raw materials for recycling, and the filter residue after natural cooling to room temperature was washed three times with 5 ml of ethanol, and then vacuum dried at 85°C to constant weight to obtain 0.34 g of yellow solid. The structure of the solid was determined by nuclear magnetic resonance hydrogen spectrum and infrared spectrum analysis to be 8-chloro-11-(4-methoxyphenyl)-5,11-dihydro-12H-benzo[b]indeno[1,2-e][1,4]oxazepine -12-ketone; the purity was 99.4% as determined by high performance liquid chromatography, and finally 8-chloro-11-(4-methoxyphenyl)-5,11-dihydro-12H-benzo[b]indeno[1,2-e][1,4]oxazepine was obtained by calculation. The yield of -12-ketone was 86%.

[0084] mp: 227~229℃; 1 H NMR (400MHz, DMSO-d6): δ10.27 (s, 1H), 7.52~7.96 (m, 3H), 7.14~7.49 (m, 4H), 6.6 3~6.90 (m, 4H), 6.32 (s, 1H), 3.65 (s, 3H)ppm; IR (KBr): ν3303, 1661, 1614, 1591cm -1 .

[0085] Example 10

[0086] 8-Bromo-11-(2,4-dichlorophenyl)-5,11-dihydro-12H-benzo[b]indeno[1,2-e][1,4]oxazepine -12-Keto

[0087]

[0088] At room temperature, first, 1.0 mmol 2-amino-5-bromophenol and 1.0 mmol 1,3-indandione were added to a 50 mL four-necked flask with a magnetic stirrer, a spherical condenser and a thermometer containing 12 g of an acidic low eutectic solvent (n (choline chloride): n (p-toluenesulfonic acid) = 1:3) in sequence, and then heated in a methyl silicone oil bath to 87°C under stirring, and monitored by TLC (thin plate chromatography). When the raw material point disappears, the heat preservation reaction time is 34 min. Immediately add 1.0 mmol 2,4-dichlorobenzaldehyde, continue stirring and heating to 85°C, and monitor by TLC (thin plate chromatography). When the raw material point disappears, the heat preservation reaction time is 54 min. Immediately stop stirring, cool naturally to 40°C, and filter under reduced pressure to obtain a filtrate and a filter residue. The filtrate was directly added to the reaction raw materials for recycling, and the filter residue after natural cooling to room temperature was washed three times with 5 ml of ethanol, and then vacuum dried at 85°C to constant weight to obtain 0.44 g of light yellow solid. The structure of the solid was determined by nuclear magnetic resonance hydrogen spectrum and infrared spectrum analysis to be 8-bromo-11-(2,4-dichlorophenyl)-5,11-dihydro-12H-benzo[b]indeno[1,2-e][1,4]oxazepine -12-ketone; the purity was 99.3% as determined by high performance liquid chromatography, and finally 8-bromo-11-(2,4-dichlorophenyl)-5,11-dihydro-12H-benzo[b]indeno[1,2-e][1,4]oxazepine was obtained by calculation. The yield of -12-ketone was 92%.

[0089] mp: 260~262℃; 1 H NMR (400MHz, DMSO-d6): δ10.48 (s, 1H), 7.64~7.95 (m, 3H), 7.19~7.63 (m, 4H), 6.64~7.14 (m, 3H), 6.47 (s, 1H)ppm; IR (KBr): ν3281, 1662, 1596, 1571cm -1 .

[0090] Examples 11 to 15

[0091] Recyclable properties of acidic deep eutectic solvents

[0092] The specific experimental process and detection method are the same as those in Example 8, except that the catalyst used is the filtrate in Example 8. Four recycling experiments were carried out under the same conditions, and the results are shown in Table 1.

[0093] Table 1

[0094]

[0095] From the data in Table 1, it can be found that: considering economic efficiency, when the liquid chromatography purity of the product is lower than 98.5% or the yield decreases by more than 5%, the acidic deep eutectic solvent should not be recycled, and the catalytic system of Example 8 can be used up to 5 times. In addition, as the number of times the acidic deep eutectic solvent is used increases, the purity and yield both slowly decrease, which is due to the decrease in catalyst activity and the gradual accumulation of by-product content.

[0096] Example 16

[0097] Regeneration of acidic deep eutectic solvents

[0098] The acidic low eutectic solvent used five times in Example 15 was used as a probe experiment to react substituted o-aminophenol, β-cyclic diketone and substituted benzaldehyde to prepare fused polycyclic 1,5-benzoxazepine Regeneration test of the low eutectic solvent in the derivatization process: add 20 ml of ethyl acetate to the filtrate of Example 15 that has stopped recycling, heat under reflux for 30 min under magnetic stirring, stop stirring, separate the liquid with a separatory funnel, then add 20 ml of ethyl acetate to the lower layer of liquid, continue to heat under reflux for 30 min under magnetic stirring, stop stirring, separate the liquid with a separatory funnel, and perform this three times in total. The lower layer of liquid obtained was vacuum dried at 85° C. for 8 h to form a regenerated acidic low eutectic solvent.

[0099] Examples 17 to 20

[0100] Recyclable performance of regenerated acidic deep eutectic solvents

[0101] The specific experimental process and detection method are the same as those of Examples 11 to 15, except that the catalyst used is the acidic deep eutectic solvent regenerated in Example 16. Three recycling experiments were carried out under the same conditions, and the results are shown in Table 2.

[0102] Table 2

[0103] #imgpt70#

[0104] From the data in Table 2, it can be found that: considering economic efficiency, when the liquid chromatography purity of the product is lower than 98.5% or the yield decreases by more than 5%, the acidic deep eutectic solvent should not be recycled, and the regenerated acidic deep eutectic solvent can be used up to 3 times.

[0105] The above specific implementation method part specifically introduces the analytical method involved in the present invention. It should be noted that the above introduction is only to help those skilled in the art better understand the method and ideas of the present invention, rather than limiting the relevant content. Without departing from the principle of the present invention, those skilled in the art may also make appropriate adjustments or modifications to the present invention, and the above adjustments and modifications shall also fall within the scope of protection of the present invention.

Claims

1. Preparation of drug intermediate 1,5-benzoxazepine catalyzed by an acidic deep eutectic solvent The method of producing a derivative, characterized in that The following steps are involved: Substituted o-aminophenol and β-cyclic diketone are used as reaction raw materials, heated to a certain temperature in an acidic low eutectic solvent, and kept warm to react until the substituted o-aminophenol disappears, and then substituted benzaldehyde is added and continued to be heated to a predetermined temperature, and kept warm to react until the aldehyde disappears, and the filter is filtered while hot, and the filter residue is washed with ethanol and then vacuum dried to obtain 1,5-benzoxazine containing a fused polycyclic structure. derivative; The chemical reaction formula of the above reaction is:

2. Preparation of pharmaceutical intermediate 1,5-benzoxazepine catalyzed by an acidic deep eutectic solvent according to claim 1 The method of producing a derivative, characterized in that The specific operation process of the above preparation method is: adding a preset volume of an acidic deep eutectic solvent into a three-necked flask at room temperature, and then adding substituted o-aminophenol and β-cyclic diketone in sequence under magnetic stirring to form a reaction system; Then proceed as follows: heat the reaction system to a preset temperature under magnetic stirring and keep warm until the reaction is complete → add substituted benzaldehyde and continue to heat to a preset temperature, keep warm until the reaction is complete → naturally cool to 40°C and filter under reduced pressure → wash the filter residue with ethanol and then vacuum dry to obtain 1,5-benzoxazine containing a fused polycyclic structure Derivatives → filtrate is directly recycled → filtrate that cannot be recycled is regenerated.

3. Preparation of pharmaceutical intermediate 1,5-benzoxazepine catalyzed by an acidic deep eutectic solvent according to claim 2 The method of producing a derivative, characterized in that The specific operation of heating the reaction system to a preset temperature under magnetic stirring and keeping the temperature until the reaction is complete is as follows: heating the reaction system to 72-87° C. in a methyl silicone oil bath under magnetic stirring, maintaining the temperature until the reaction is complete, stirring continuously during the keeping temperature, and the keeping temperature reaction time is 23-34 minutes; The specific operation of adding substituted benzaldehyde and heating to the preset temperature and keeping the temperature until the reaction is complete is as follows: continue to add substituted benzaldehyde to the reaction system and heat to 78-85°C, maintain this temperature until the reaction is complete, continue stirring during the insulation process, and the insulation reaction time is 31-54 minutes; The specific operation of vacuum filtration when the temperature naturally drops to 40°C is as follows: immediately stop stirring, vacuum filtration when the temperature naturally drops to 40°C, vacuum filtration to obtain filter residue and filtrate; The filter residue was washed with ethanol and then dried in vacuum to obtain 1,5-benzoxazine containing a fused polycyclic structure. The specific operation of the derivative is: washing the filter residue with ethanol three times, and then vacuum drying at 85°C to constant weight to obtain 1,5-benzoxazine derivative; The specific operation of directly recycling the filtrate is: the filtrate is directly added to the reaction raw materials without any treatment to carry out the next round of reaction, and the filtrate is recycled for multiple times. The 1,5-benzoxazine obtained in each cycle The purity of the derivatives was monitored by high performance liquid chromatography and the yield was calculated. When the purity was lower than 98.5% or the yield decreased by more than 5%, the recycling was stopped. The specific operation of regenerating the filtrate that cannot be recycled is as follows: adding a preset volume of ethyl acetate to the filtrate that has stopped recycling, heating and reflux for 30 minutes under magnetic stirring, stopping stirring, separating the liquid with a separatory funnel, and then adding the same volume of ethyl acetate to the lower layer of liquid, continuing to heat and reflux for 30 minutes under magnetic stirring, stopping stirring, separating the liquid with a separatory funnel, and performing this operation three times in total; vacuum drying the lower layer of liquid obtained at 85° C. for 8 hours to form a regenerated acidic low eutectic solvent; wherein the volume usage of ethyl acetate is 1 to 3 times the mass usage of the acidic low eutectic solvent.

4. Preparation of pharmaceutical intermediate 1,5-benzoxazepine catalyzed by an acidic deep eutectic solvent according to claim 1 The method of producing a derivative, characterized in that The acidic low eutectic solvent is composed of choline chloride and p-toluenesulfonic acid, wherein the molar ratio of choline chloride to p-toluenesulfonic acid is 1:

3.

5. Preparation of pharmaceutical intermediate 1,5-benzoxazepine catalyzed by an acidic deep eutectic solvent according to claim 1 The method of producing a derivative, characterized in that The amount of the acidic deep eutectic solvent used in grams is 8 to 12 times the molar amount of the substituted o-aminophenol in millimoles.

6. Preparation of pharmaceutical intermediate 1,5-benzoxazepine catalyzed by an acidic deep eutectic solvent according to claim 1 The method of producing a derivative, characterized in that The substituted o-aminophenol is selected from Any of .

7. Preparation of pharmaceutical intermediate 1,5-benzoxazepine catalyzed by an acidic deep eutectic solvent according to claim 1 The method of producing a derivative, characterized in that The substituted benzaldehyde is selected from Any of .

8. Preparation of pharmaceutical intermediate 1,5-benzoxazepine catalyzed by an acidic deep eutectic solvent according to claim 1 The method of producing a derivative, characterized in that The molar ratio of the substituted o-aminophenol, the beta-cyclic diketone and the substituted benzaldehyde is 1:1:

1.

9. A method for preparing a pharmaceutical intermediate 1,5-benzoxazepine catalyzed by an acidic deep eutectic solvent according to claim 1 The method of producing a derivative, characterized in that The β-cyclic diketone is 1,3-cyclopentanedione or 1,3-indandione.

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