Method for preparing o-benzoyl aniline by using benzoyl derivative

Abstract

The invention provides a method for synthesizing o-benzoyl aniline by using a benzoyl derivative, which comprises the following steps: reacting phthalimide with a compound in a formula II according to a specific ratio to prepare 2-hydroxy-2-phenylindole-5-ketone (in a formula III), and then carrying out Hofmann degradation reaction to obtain the o-benzoyl aniline (in a formula IV). According to the method, the alkaline-oxidation condition is adopted, Hoffman oxidation rearrangement is achieved while ring opening is conducted, the target product is obtained, and the total yield is 72%. Compared with a previously designed synthesis route, the method has the advantages of simple steps, mild reaction conditions and high feasibility, and has industrial development prospects.

Description

Technical Field

[0001] The invention belongs to organic synthesis, and specifically relates to a method for preparing o-benzanilide by using benzoyl derivatives. Background Art

[0002] o-Benzylaniline is a derivative of benzophenone, used to make antihistamines, hypnotics and insecticides. It is an important intermediate in the synthesis of the antidepressant 11-(3-dimethylaminopropyl)-6-phenyl-11H-pyrido[2,3-B][1,4]benzodiazepine. The structural formula of o-Benzylaniline is as follows:

[0003]

[0004] At present, the preparation of o-phenylaniline mainly includes the following methods.

[0005] 1) o-Benzanilide is prepared by reacting benzanilide with acetonitrile. This method requires ultraviolet light, has a long reaction time, low selectivity, low yield and high cost; its chemical reaction formula is as follows:

[0006]

[0007] 2) Aniline is used as a raw material and first subjected to Friedel-Crafts reaction and then to enhanced acid hydrolysis to obtain o-phenylaniline. This method has harsh reaction conditions, large catalyst dosage, long time consumption and low yield. The chemical reaction formula is as follows: Summary of the invention

[0008] In order to solve the problems in the prior art, the present invention provides a method for preparing o-benzanilide using benzoyl derivatives. 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.

[0009] The present invention adopts the following technical solution:

[0010] A method for synthesizing o-benzanilide using a benzoyl derivative, wherein a benzoyl derivative compound of formula I and a compound of formula II are reacted to obtain a compound of formula III, and then the compound of formula III is ring-opened to obtain o-benzanilide (formula IV). The synthesis route is as follows:

[0011]

[0012] Studies have found that in the process of using a benzoyl derivative compound of formula I to react with a compound of formula II to obtain a compound of formula III, the raw material feed ratio has a very important influence on the reaction.

[0013]

[0014] During the experiment, the molar ratio of the compound of formula II to the compound of phthalimide formula I was 2:1, and the best effect was achieved. The compound of formula II was slowly added dropwise at room temperature, and then condensed and refluxed at a reaction temperature of 60°C for 1 hour, resulting in more by-products. Later, it was found that the reaction was slowly added dropwise under ice bath conditions, and then reacted at room temperature to produce the compound of formula III, resulting in fewer by-products and a shorter reaction time.

[0015] According to one embodiment of the present invention, the molar ratio of the compound of formula II to the phthalimide compound of formula I is 2: 1. Further, the compound of formula II is added dropwise under ice bath conditions, and then reacted at room temperature to generate the compound of formula III.

[0016] In the process of ring opening of the compound of formula III to obtain o-phenylaniline (formula IV), a strong acid is added to open the ring, and the obtained compound is separated and purified. 1 H-NMR, 13 C-NMR confirmed that its structure was 2-phenylindole-5-one (Formula V), and the ring was not opened, but a dehydrated product was obtained.

[0017]

[0018] After the acidic ring opening fails, the compound of formula III is subjected to a ring opening-rearrangement reaction under alkaline oxidation with sodium hypochlorite and sodium hydroxide. After the reaction is complete, the compound is separated and purified to obtain the compound. 1 H-NMR, 13 C-NMR confirmed that its structure was o-benzanilide (Formula IV).

[0019] According to one embodiment of the present invention, the compound of formula III is ring-opened under alkaline oxidation conditions to obtain o-benzanilide (formula IV). Further, the alkaline oxidation conditions are sodium hypochlorite and sodium hydroxide. Further, the alkaline oxidation conditions are a 4% sodium hypochlorite aqueous solution and a 20% sodium hydroxide aqueous solution.

[0020] Beneficial effects:

[0021] The present invention provides a method for synthesizing o-benzanilide using benzoyl derivatives, wherein 2-hydroxy-2-phenylindole-5-one (Formula III) is prepared by reacting o-phthalimide with a compound of Formula II in a specific ratio, and then o-benzanilide (Formula IV) is obtained by Hoffman degradation reaction. The present invention adopts alkaline-oxidation conditions, realizes Hoffman oxidation rearrangement while opening the ring, and obtains the target product with a total yield of 72%. Compared with the previously designed synthetic route, the present method has simple steps, mild reaction conditions, high feasibility, and the price of the obtained o-benzanilide is much lower than the commercial price of 760 yuan / kg, and has industrial development prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 is the hydrogen spectrum of compound 4 (2-hydroxy-2-phenylindole-5-one);

[0023] Figure 2 Carbon spectrum of compound 4 (2-hydroxy-2-phenylindole-5-one);

[0024] Figure 3 Hydrogen spectrum of compound 5 (2-phenylindol-5-one);

[0025] Figure 4 Carbon spectrum of compound 5 (2-phenylindol-5-one);

[0026] Figure 5 Hydrogen spectrum of compound 6 (o-benzylaniline);

[0027] Figure 6 Carbon spectrum of compound 6 (o-benzylaniline). DETAILED DESCRIPTION

[0028] 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.

[0029] Instruments and reagents

[0030] Table 1 Main instruments

[0031]

[0032]

[0033] Table 2 Main reagents

[0034]

[0035] Synthesis of Grignard Reagents

[0036] Example 1

[0037] The chemical reaction formula is as follows:

[0038]

[0039] Under N2 protection, magnesium strip (0.59g, 24.5mmol), THF (20mL) and an appropriate amount of iodine were added to a 100mL two-necked bottle and reacted in an oil bath at 70°C. After stirring and initiation, bromobenzene (2.2mL, 20.4mmol) and THF (15mL) were mixed and slowly added dropwise to the reaction bottle to maintain the reaction. After the dropwise addition, the reaction was condensed and refluxed for 6h. The metal magnesium strip disappeared, and the reaction was completed to obtain bromobenzene Grignard reagent.

[0040] Synthesis of o-benzanilide from benzoyl derivatives:

[0041] During the experiment, phthalimide was reacted with bromobenzene Grignard reagent to generate compound 4. The molar ratio of bromobenzene Grignard reagent to phthalimide was 2:1, which was the best. Bromobenzene Grignard reagent was slowly added dropwise at room temperature, and then condensed and refluxed at a reaction temperature of 60°C for 1h. The synthesized by-products were relatively large. Later, it was found that the reaction was carried out under ice bath conditions. The bromobenzene Grignard reagent was slowly added dropwise, and then reacted at room temperature to generate compound 4. The synthesized by-products were relatively small and the time consumption was shorter. The isolated and purified compound 4 was then 1 H-NMR, 13 C-NMR confirmed that its structure is 2-hydroxy-2-phenylindole-5-one ( Figure 1-Figure 2 ), not ring-opened, not the expected compound 2-benzoylbenzophenone, which may be because the amide bond in the phthalimide structure is too stable and difficult to break. Its chemical reaction formula is as follows:

[0042]

[0043] In order to open the ring, after the phthalimide and bromobenzene Grignard reagent reacted completely, a strong acid was added to open the ring, and the obtained compound 5 was separated and purified. 1 H-NMR, 13 C-NMR confirmed that its structure is 2-phenylindole-5-one ( Figure 3-Figure 4 ), and the ring is not opened, and the product obtained is a dehydrated product. The chemical reaction formula is as follows:

[0044]

[0045] After the acidic ring opening failed, the inventors subjected compound 4 to a ring opening-rearrangement reaction under alkaline oxidation with sodium hypochlorite and sodium hydroxide. After the reaction was complete, compound 6 was separated and purified. 1 H-NMR, 13 C-NMR confirmed that its structure was o-benzylaniline ( Figure 5-Figure 6 ). Its chemical reaction formula is as follows:

[0046]

[0047] Example 2

[0048] Reaction route:

[0049]

[0050] Phthalimide (1.5 g, 10 mmol) and THF (40 mL) were added to a 100 mL two-necked round-bottom flask under N2 protection. In an ice bath, the prepared bromobenzene Grignard reagent (20 mmol) was slowly added dropwise to the reaction flask. After the addition, the reaction was allowed to react at room temperature for 30 min. The reaction solution was transferred to a separatory funnel, and ethyl acetate was added to terminate the reaction. The reaction solution was washed with saturated NaHCO3 and saturated NaCl, and the organic layer was collected and dried with anhydrous Na2SO4. The solid (Compound III, 1.79 g) was separated by column chromatography (dichloromethane: ethyl acetate = 2:1) with a yield of 80%. 1 H-NMR (600MHz, DMSO-d6): δ9.23(s,1H),7.64(m,1H),7.52(td,J=1,7.4,1H),7.48-7.45(m,3H),7.34(m,2H),7.30-7.27(m,2H),8.89(s,1H). 13 C-NMR (150MHz, DMSO-d6): δ168.8,151.3,142.6,132.8,131.1,129.4,128.7,128.7,128.2,125.9,125.9,123.2,123.0,87.8.

[0051] Compound III (1.79 g) was added to 3 mL of water, and 15 mL of a 4% sodium hypochlorite aqueous solution and 6 mL of a 20% sodium hydroxide solution were added dropwise in sequence. After the addition was completed, the temperature was raised to 90°C and kept warm for 30 min until the reaction was complete. An appropriate amount of water was added, and the mixture was cooled, filtered, washed with water, and dried to obtain a crude compound IV. The product 1.21 g (compound IV) was separated by column chromatography (petroleum ether: dichloromethane = 4:1) with a content of 98.9% and a yield of 77%. 1 H-NMR (600MHz, DMSO-d6): δ7.56-7.51(m,5H),7.31-7.24(m,2H),7.11(s,2H),6.89(dd,J=8.3,0.7Hz,1H),6.50(m,1H). 13 C-NMR (150MHz, DMSO-d6): δ197.8,151.6,139.9,134.0,133.5,130.6,128.3,128.3,128.0,128.0,116.8,116.2,114.2.

[0052] Refer to the reaction route of Example 2 to prepare Examples 3-4.

[0053] Example 3

[0054] Phthalimide (10 g) and THF (20 mL) were added to a two-mouth round-bottom flask under N2 protection. Under ice bath conditions, 34 mL of phenylmagnesium chloride (2 M) tetrahydrofuran solution was slowly added dropwise to the reaction flask. After the addition was complete, the reaction was allowed to react at room temperature for 1 hour. TLC showed that the reaction was complete. Ethyl acetate was added to terminate the reaction. The reaction solution was washed with saturated NaHCO3 and saturated NaCl, and the organic layer was collected, dried with anhydrous Na2SO4, and concentrated to obtain a solid (crude product of compound III, 11.2 g) with a yield of 73%.

[0055] Compound III (13.3 g) was added to 30 mL of water, and 200 mL of a 4% sodium hypochlorite aqueous solution and 60 mL of a 20% sodium hydroxide solution were added dropwise in sequence. After the addition was completed, the temperature was raised to 90°C and kept warm for 30 min until the reaction was complete. An appropriate amount of water was added, the mixture was cooled, filtered, and washed with water. The crude product was crystallized with an appropriate amount of ethanol to obtain the product compound IV (9.4 g) with a content of 98.3% and a yield of 81%.

[0056] Example 4

[0057] Phthalimide (1kg) and THF (2L) were added to a two-mouth round-bottom flask under N2 protection. In an ice bath, 3.4L of phenylmagnesium chloride (2M) tetrahydrofuran solution was slowly added dropwise to the reaction flask. After the addition was complete, the reaction was allowed to react at room temperature for 1 hour. TLC showed that the reaction was complete. Ethyl acetate was added to terminate the reaction. The reaction solution was washed with saturated NaHCO3 and saturated NaCl, the organic layer was collected, dried with anhydrous Na2SO4, and concentrated to obtain a solid (crude product of compound III, 1.3kg) with a yield of 84%.

[0058] Compound III (1.3 kg) was added to 3 L of water, and 20 L of 4% sodium hypochlorite aqueous solution and 6 L of 20% sodium hydroxide solution were added dropwise in sequence. After the addition was completed, the temperature was raised to 90°C and kept warm for 30 min until the reaction was complete. An appropriate amount of water was added, and the mixture was cooled, filtered, and washed with water. The crude product was crystallized with an appropriate amount of ethanol to obtain the product compound IV (0.93 kg) with a content of 98.3% and a yield of 83%.

[0059] The cost of o-benzanilide (Compound IV) prepared in Example 4 is calculated as shown in Table 3 below:

[0060] Table 3 Cost accounting of o-phenylaniline prepared in Example 4

[0061]

[0062] It can be seen from Table 3 above that the cost of preparing o-benzanilide by the present invention can reach 180 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 o-benzanilide using a benzoyl derivative, wherein a benzoyl derivative compound of formula I is reacted with a compound of formula II to obtain a compound of formula III, and then the compound of formula III is ring-opened to obtain o-benzanilide (formula IV). The synthetic route is as follows:

2. The method according to claim 1, characterized in that The molar ratio of the compound of formula II to the phthalimide compound of formula I is 2:

1.

3. The method according to claim 2, characterized in that The compound of formula II is added dropwise under ice bath conditions, and then reacted at room temperature to generate the compound of formula III.

4. The method according to any one of claims 1 to 3, characterized in that: The compound of formula III undergoes ring opening under alkaline oxidation conditions to give o-benzanilide (formula IV).

5. The method according to claim 4, characterized in that The alkaline oxidation conditions are sodium hypochlorite and sodium hydroxide.

6. The method according to claim 5, characterized in that The alkaline oxidation conditions are a sodium hypochlorite aqueous solution with a mass fraction of 4% and a sodium hydroxide aqueous solution with a mass fraction of 20%.

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