Method for synthesizing 2-aminobenzophenone by using isatoic anhydride
Through the reaction of isatin anhydride with Grignard reagent, combined with the ring opening reaction under acidic conditions, the synthesis yield of 2-aminobenzophenone and the suitability of industrial production were successfully improved, and the synthesis routes in the prior art were solved. kind of problems.
Patent Information
- Application Number
- CN202411470990.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-21
- Publication Date
- 2025-02-14
AI Technical Summary
The existing synthesis route of 2-aminobenzophenone has problems such as high reaction temperature, requiring a large amount of catalyst, long hydrolysis time, low yield, serious environmental pollution, complex operation, and low total yield, and is not suitable for industrial production.
The compound of formula 2 was obtained by reacting isatin anhydride with a specific ratio of Grignard reagent PhMgX, and then a ring-opening reaction was carried out under acidic conditions to obtain 2-aminobenzophenone.
The raw materials of this method are easy to obtain, have high reaction yields, are environmentally friendly, and have a significantly reduced final product cost, making it suitable for industrial production.
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Abstract
Description
Technical Field
[0001] The invention belongs to drug synthesis, and specifically relates to a method for synthesizing 2-aminobenzophenone by using isatoic anhydride. Background Art
[0002] 2-aminobenzophenone is an important pharmaceutical intermediate for the synthesis of benzodiazepine antidepressant tampamine. Tampamine is prepared by the reaction of 2-aminobenzophenone, 3-amino-2-chloropyridine and N-(3-chloropropyl)dimethylamine. Currently, there are several main synthetic routes for 2-aminobenzophenone:
[0003] 1) Aniline is prepared by Friedel-Crafts reaction with acyl chloride and then hydrolyzed with strong acid. This method has a high reaction temperature (215℃±15℃), requires a large amount of catalyst, and takes a long time to hydrolyze (20h±3h). The yield is 42%±2% (Li Wanfang, Deng Qinyue, Huang Mingxian. Friedel-Crafts: Great Reactions and Great Collaborators [J]. Chemical Education, 2021, 42(10): 106-111.).
[0004] 2) First, the amino group of anthranilic acid is protected with p-toluenesulfonyl chloride, then the carboxyl group is chlorinated and then subjected to Friedel-Crafts reaction, and finally hydrolyzed under strong acid conditions. This route is very likely to produce a large amount of aluminum salt waste liquid, which seriously pollutes the environment (Scheifele HJ, DeTar D F. 2-Aminobenzophenone [J]. Organic Syntheses, 1952, 32: 8-12.).
[0005] 3) Using isatin as a raw material, first react with chlorobenzene Grignard reagent to obtain 3-hydroxy-3-phenylindole-2-one, and then oxidize with hydrogen peroxide or potassium ferricyanide to obtain it. However, this route requires the use of ether to synthesize the Grignard reagent, and then remove the ether by distillation and add toluene to react with isatin. The operation is complicated and not simple, and the total yield is only 26% (Carlos Mateos, Juan A. Rincón, José Villanueva, Efficient and scalable synthesis of ketones via nucleophilic Grignard addition to nitriles using continuous flow chemistry [J]. Tetrahedron Letters 54 (2013) 2226–2230.).
[0006] The above synthetic routes involve or require ring opening or rearrangement, the reaction is difficult and hard to obtain, or the raw materials for preparation are expensive, there are many by-products, the yield is low, and there is environmental pollution in the production process, which is not suitable for industrial production. Summary of the invention
[0007] In order to solve the problems in the prior art, the present invention provides a method for synthesizing 2-aminobenzophenone using isatoic anhydride. The method has a wide source of raw materials, a high reaction yield, is relatively environmentally friendly, and significantly reduces the cost of the final product, thus having important industrial value.
[0008] The present invention adopts the following technical solution:
[0009] A method for synthesizing 2-aminobenzophenone using isatoic anhydride, wherein isatoic anhydride (Formula 1) and a Grignard reagent PhMgX are reacted to obtain a compound of Formula 2, and then the compound of Formula 2 is ring-opened to obtain 2-aminobenzophenone (Formula 3). The synthesis route is as follows:
[0010]
[0011] Wherein X is Cl or Br.
[0012] According to one embodiment of the present invention, in the above method, the Grignard reagent PhMgX is prepared by reacting chlorobenzene or bromobenzene with activated magnesium flakes, and the reaction temperature is 60-80°C; further, the reaction temperature is 70-75°C.
[0013] According to one embodiment of the present invention, in the above method, the reaction solvent is methyltetrahydrofuran.
[0014] The study found that in the process of using isatoic anhydride (Formula 1) and Grignard reagent PhMgX to react to obtain the compound of Formula 2, the raw material feed ratio has a very important influence on the reaction. The Grignard reagent PhMgX: isatoic anhydride is 1:1 (10mmol: 10mmol), 2:1 (20mmol: 10mmol) and 3:1 (30mmol: 10mmol), and the TLC spot plate is used for monitoring. At 1:1, there is still a large amount of raw material that has not reacted, and the reactions of 2:1 and 3:1 are more thorough. After the reaction with Grignard reagent PhMgX: isatoic anhydride = 3:1, the sample is mixed with silica gel and then separated by column chromatography (ethyl acetate: methanol = 10:1). During the spot plate monitoring, ethyl acetate: methanol = 4:1 is used as the developing solvent ratio. The pure separated product is sent to the nuclear magnetic spectrum, which shows that the anhydride ring does not open as expected to generate 2-aminobenzophenone, but generates 4-hydroxy-4-phenyl-1,4-dihydro-2H-benzo[d][1,3]oxazine-2-one (Formula 4). The structural formula of 4-hydroxy-4-phenyl-1,4-dihydro-2H-benzo[d][1,3]oxazine-2-one (Formula 4) is as follows:
[0015]
[0016] According to one embodiment of the present invention, in the process of using isatoic anhydride (Formula 1) and Grignard reagent PhMgX to react to obtain the compound of Formula 2, the molar ratio of Grignard reagent PhMgX:isatoic anhydride is 1-3:1; preferably 2:1.
[0017] The study found that in the process of ring-opening the compound of Formula 2 to obtain 2-aminobenzophenone (Formula 3), the inventors hydrolyzed the compound of Formula 2 in methanol / hydrochloric acid and methanol / sodium hydroxide systems respectively to open the ring. Under alkaline conditions, more by-products were produced, while the ring-opening reaction under acidic conditions was more ideal.
[0018] According to one embodiment of the present invention, the compound of formula 2 is reacted under acidic conditions to obtain 2-aminobenzophenone (formula 3); preferably, the acid is hydrochloric acid.
[0019] Beneficial effects:
[0020] The present invention provides a method for synthesizing 2-aminobenzophenone by using isatoic anhydride. The present invention uses isatoic anhydride, which is easily available as a raw material, as a raw material to prepare 2-aminobenzophenone, and reacts with a Grignard reagent PhMgX in a specific proportion to obtain a new compound of formula 2, and then opens the ring under acidic conditions to obtain 2-aminobenzophenone, with a yield of 68%, which is significantly improved compared with the prior art. The raw materials of this route are cheap and easily available, the operation is simple, the equipment requirements are low, and the product is easy to separate. The price of the obtained 2-aminobenzophenone is much lower than the commercial price of 760 yuan / kg, which is very suitable for industrial production. DETAILED DESCRIPTION
[0021] In order to further illustrate the present invention and its advantages, the technical scheme of the present invention is further illustrated by specific embodiments below, and it should be understood that these embodiments only help to understand the present invention and should not be regarded as specific limitations of the present invention. The raw materials and reagents used in the present invention are all commercially available products. Unless otherwise specified, the parts described in the present invention are all weight parts, and the percentages are all mass percentages.
[0022] Preparation of Grignard reagent
[0023] Example 1
[0024] N 2 Under protection, 0.49 g (20.4 mmol) of magnesium was added to 5 mL of methyltetrahydrofuran, and an appropriate amount of I 2 As an initiator. Place in an oil bath heated to 75°C, slowly drop 15 mL of methyltetrahydrofuran solution mixed with 20.4 mmol of bromobenzene, stir, and heat under reflux until the magnesium flakes disappear, to prepare the Grignard reagent PhMgBr.
[0025] PhMgCl was prepared according to Example 1.
[0026] Preparation of 2-aminobenzophenone
[0027] The route is as follows:
[0028]
[0029] The study found that in the process of using isatoic anhydride (Formula 1) and Grignard reagent PhMgX to react to obtain the compound of Formula 2, the raw material feed ratio has a very important influence on the reaction. The Grignard reagent PhMgX: isatoic anhydride is 1:1 (10mmol: 10mmol), 2:1 (20mmol: 10mmol) and 3:1 (30mmol: 10mmol), and TLC spot plate monitoring is performed. At 1:1, there is still a large amount of raw material that has not reacted, and 2:1 and 3:1 react more thoroughly. After the reaction with Grignard reagent PhMgX: isatoic anhydride = 3:1, the sample is mixed with silica gel and then separated by column chromatography (ethyl acetate: methanol = 10:1). During spot plate monitoring, ethyl acetate: methanol = 4:1 is used as the developing solvent ratio. The pure separated product is sent to nuclear magnetic resonance spectroscopy, which shows that the anhydride ring does not open as expected to generate 2-aminobenzophenone, but instead generates 4-hydroxy-4-phenyl-1,4-dihydro-2H-benzo[d][1,3]oxazine-2-one.
[0030] The inventors also found that in the process of ring-opening the compound of Formula 2 to obtain 2-aminobenzophenone (Formula 3), the inventors hydrolyzed the compound of Formula 2 in methanol / hydrochloric acid and methanol / sodium hydroxide systems, respectively. There were many by-products under alkaline conditions, while the ring-opening reaction under acidic conditions was more ideal.
[0031] The operating steps for preparing 2-aminobenzophenone are the same as those in Example 2-4.
[0032] Example 2
[0033] N 2 Under ice-water bath conditions, 20 mL (1 mmol / mL) of phenylmagnesium bromide solution was added to a two-necked flask containing 1.63 g (10 mmol) of isatoic anhydride in tetrahydrofuran (20 mL). After stirring for 0.5 hours, the reaction was monitored by TLC. 10 ml of ethyl acetate was added to terminate the reaction, and then washed with an appropriate amount of saturated sodium bicarbonate solution and saturated sodium chloride solution, dried, and evaporated under reduced pressure. The residue was separated by silica gel column chromatography (ethyl acetate: methanol = 10:1) to obtain 1.79 g of solid (compound 2, yield 75%). 1 H-NMR (600MHz, DMSO-d6): δ11.10(s,1H),8.70(dd,J=8.2,0.8Hz,1H),8.08(dd,J=7.7,1 .4Hz,1H),8.02(m,2H),7.61(m,1H),7.56(m,2H),7.48(m,1H),7.09(m,1H),5.50(s,1H).13 C-NMR (150MHz, DMSO-d6): δ164.2,140.9,134.9,131.7,131.6,131.2,128.7,128.7,128.6,127.0,127.0,122.0,118.8,110.8.
[0034] Add 1g of compound 2 in methanol (20mL) to the reaction flask, then add 5mL of concentrated hydrochloric acid, stir and reflux, monitor the reaction progress by TLC, and the reaction is complete after 2 hours. The reaction solution is concentrated under reduced pressure, 40ml of ethyl acetate is added to the residue, and then washed with an appropriate amount of saturated sodium bicarbonate solution and saturated sodium chloride solution, dried, distilled under reduced pressure, and separated by silica gel column chromatography (dichloromethane: ethyl acetate = 2: 1) to obtain 0.74g of compound 3 solid, with a content of 99.2% and a yield of 91%. 1 H-NMR (600MHz, DMSO-d6): δ7.58-7.50(m,5H),7.29-7.25(m,2H),7.11(s,2H),6.86(dd,J=8.2,0.7Hz,1H),6.50(m,1H). 13 C-NMR (150MHz, DMSO-d6): δ197.8,151.8,139.9,134.1,133.7,130.8,128.4,128.4,128.1,128.1,116.8,116.2,114.0.
[0035] Example 3
[0036] N 2 Under ice-water bath conditions, 30 mL of phenylmagnesium chloride (2M) methyltetrahydrofuran solution was added to a reaction bottle containing isatoic anhydride (10 g) in tetrahydrofuran (20 mL), and stirred in an ice-water bath for 1 hour. TLC showed that the reaction was complete. An appropriate amount of ethyl acetate was added to terminate the reaction. The reaction solution was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried, and evaporated under reduced pressure to obtain a white solid (crude product of compound 2, 13.3 g).
[0037] 13.3 g of the crude product of compound 2 was added to a reaction flask containing 40 mL of hydrochloric acid (2 M), stirred and refluxed for 4 hours. TLC showed that the reaction was completed. The temperature was cooled to room temperature, 40 mL of sodium hydroxide aqueous solution (2 M) was added, filtered, the solid was washed with water, dried, and then an appropriate amount of ethanol was added for crystallization to obtain 10.5 g of the product with a content of 97.1% and a yield of 87%.
[0038] Embodiment 4:
[0039] N 2Under ice-water bath conditions, 3 L of phenylmagnesium chloride (2M) methyltetrahydrofuran solution was added to a reaction bottle containing isatoic anhydride (1 kg) in tetrahydrofuran (2 L), and stirred in an ice-water bath for 1.5 hours. TLC showed that the reaction was complete. An appropriate amount of ethyl acetate was added to terminate the reaction. The reaction solution was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried, and evaporated under reduced pressure to obtain a white solid (crude product of compound 2, 1.4 kg).
[0040] 1.4 kg of crude compound 2 was added to a reaction flask containing 4 L of hydrochloric acid (2 M), stirred and refluxed for 6 hours. TLC showed that the reaction was completed. The temperature was cooled to room temperature, 4 L of sodium hydroxide aqueous solution (2 M) was added, filtered, the solid was washed with water, dried, and then an appropriate amount of ethanol was added for crystallization to obtain 1.04 kg of product with a content of 96.7% and a yield of 86%.
[0041] The cost of 2-aminobenzophenone prepared in Example 4 is calculated as shown in Table 1 below:
[0042] Table 1 Cost accounting of 2-aminobenzophenone prepared in Example 4
[0043]
[0044] As can be seen from Table 1 above, the cost of preparing 2-aminobenzophenone according to the present invention can reach 245 yuan / kg, which is far lower than the market price of 760 yuan / kg (chemical raw material procurement inquiry website: www.chemicalbook.com), and the cost is greatly reduced, which is suitable for industrial production.
Claims
1. A method for synthesizing 2-aminobenzophenone using isatoic anhydride, wherein isatoic anhydride (Formula 1) and Grignard reagent PhMgX are reacted to obtain a compound of Formula 2, and then the compound of Formula 2 is ring-opened to obtain 2-aminobenzophenone (Formula 3). The synthesis route is as follows: Wherein X is Cl or Br.
2. The method according to claim 1, characterized in that: The Grignard reagent PhMgX is prepared by reacting bromobenzene or chlorobenzene with activated magnesium flakes at a reaction temperature of 60-80°C.
3. The method according to claim 2, characterized in that: The reaction temperature is 70-75°C.
4. The method according to claim 2, characterized in that: The reaction solvent is methyltetrahydrofuran.
5. The method according to any one of claims 1 to 4, characterized in that: The molar ratio of the Grignard reagent PhMgX to isocyanic anhydride is 1-3:
1.
6. The method according to claim 5, characterized in that: The molar ratio of the Grignard reagent PhMgX to isocyanic anhydride is 2:
1.
7. The method according to any one of claims 1 to 4, characterized in that: The compound of formula 2 reacts under acidic conditions to obtain 2-aminobenzophenone (formula 3).
8. The method according to claim 7, characterized in that: The acid is hydrochloric acid.
9. The method according to claim 1, characterized in that: Isatoic anhydride (Formula 1) and Grignard reagent PhMgX are reacted to obtain a compound of Formula 2, and then the compound of Formula 2 is ring-opened to obtain 2-aminobenzophenone (Formula 3). The synthetic route is as follows: The Grignard reagent PhMgX is prepared by reacting bromobenzene or chlorobenzene with activated magnesium flakes, the reaction temperature is 70-75°C, and the reaction solvent is methyltetrahydrofuran; the feeding molar ratio of the Grignard reagent PhMgX: isatoic anhydride is 2:1; the compound of formula 2 reacts under acidic conditions to obtain 2-aminobenzophenone (formula 3), and the acid is hydrochloric acid.