A kind of synthetic method of 4-acetyl-1-naphthoic acid

Abstract

The present invention belongs to the technical field of organic synthesis, and specifically relates to a method for synthesizing 4-acetyl-1-naphthoic acid, a key intermediate of afolan. The method uses 1-methylnaphthalene as a starting material, first undergoes a Friedel-Crafts acylation reaction to obtain an intermediate 4-acetyl-1-methylnaphthalene, and then undergoes methyl oxidation to obtain the target product 4-acetyl-1-naphthoic acid. The method of the present invention is simple to operate, has low requirements for equipment, and uses more friendly reagents; avoids the use of highly toxic cyanide and the risk of high-temperature equipment; the yield is also higher and environmentally friendly.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing 4-acetyl-1-naphthoic acid, a key intermediate of afoxol. Background Art

[0002] 4-Acetyl-1-naphthoic acid is a key intermediate of the insect repellent afolan. Chemical formula of 4-Acetyl-1-naphthoic acid: C 13 H 10 O3, English name 4-acetyl-1-naphthoic acid, CAS No: 131986-05-5, structural formula:

[0003] .

[0004] According to rough statistics, the number of registered pet dogs in China has exceeded 75 million, of which more than 55 million are kept in urban areas. Pet dogs are active, like to play around, smell and lick, and are very susceptible to parasitic diseases, skin diseases, infectious diseases, etc., among which parasitic diseases are the most common. Common external parasites include ticks and fleas, and internal parasites include heartworms, roundworms, hookworms, whipworms, etc., which not only affect the physical and mental health of pets, but also pollute the environment due to their strong reproductive capacity, thus posing a hidden danger to human health; in addition, it also greatly reduces the willingness of pet owners to have close contact with their pets. Therefore, it is particularly important to prevent and treat parasitic diseases in pet dogs.

[0005] Afoxolaner, trade name NexGard, is the first oral dog anthelmintic launched in China by Boehringer Ingelheim in August 2017. It targets both ticks and fleas. It can meet the needs of pet owners to "take care of both inside and outside". Dogs only need to take it once a month to eliminate and prevent six major types of common parasites inside and outside the body, including heartworms, roundworms, hookworms, whipworms, fleas, and ticks. It belongs to the isoxazoline class of compounds, and its working principle is to inhibit the GABA chloride channel of arthropods, thereby causing death due to high nerve excitement. Two hours after taking Afoxolaner, fleas begin to be killed, making it impossible for fleas to lay eggs, avoiding environmental pollution, and can effectively prevent fleas from laying eggs for five weeks. At the same time, it can kill 8 common cicada insects, and the effect lasts for more than one month. At present, the market development of this drug in the field of pet anthelmintics is good.

[0006] Patent CN115448831A discloses a synthesis process of 4-acetyl-1-naphthoic acid, which specifically uses 1-bromonaphthalene as the starting material, obtains 4-acetyl-1-naphthoacetone through Friedel-Crafts acylation, then obtains acetal through p-toluenesulfonic acid and methanol, and finally obtains 4-acetyl-1-naphthoic acid through Grignard reaction and acidification. This method has a low yield and requires the use of n-butyl lithium, which is expensive and dangerous. The technical route in this document is as follows:

[0007] .

[0008] Patent CN113354530A discloses a method of using 1,4-naphthalene dicarboxylic acid as a starting material to obtain 4-acetyl-1-naphthoic acid through esterification-hydrolysis-condensation-hydrolysis-hydrolysis. This route has many steps, and the post-processing is relatively cumbersome, and the actual scale-up operation will have disadvantages. The technical route in this document is as follows:

[0009] .

[0010] The document Justus Liebigs Annalen der Chemie, 1932, vol, p.99, 115 reported that 4-acetyl-1-bromonaphthalene was used as the starting material to obtain 4-acetyl-1-naphthoic acid through cyanation-hydrolysis. The disadvantages of this route are that highly toxic potassium cyanide is required, the reaction temperature is 200°C, and sulfuric acid is used during hydrolysis. Sulfuric acid is highly corrosive to equipment and is not conducive to industrial production. The technical route in this document is as follows:

[0011] Summary of the invention

[0012] The technical problem solved by the invention is to provide a new synthesis method of 4-acetyl-1-naphthoic acid which is environment-friendly, short in steps and simple in operation.

[0013] The present invention is achieved through the following technical solutions:

[0014] A method for synthesizing 4-acetyl-1-naphthoic acid, wherein the synthesis reaction route is as follows:

[0015] .

[0016] The method uses 1-methylnaphthalene as a starting material, first undergoes a Friedel-Crafts acylation reaction to obtain an intermediate 4-acetyl-1-methylnaphthalene (step 1), and then undergoes methyl oxidation (step 2) to obtain the target product 4-acetyl-1-naphthoic acid.

[0017] The synthetic method of the above-mentioned 4-acetyl-1-naphthoic acid comprises the following steps:

[0018] (1) Add solvent to the reaction vessel, cool to below 0°C, add catalyst, slowly dropwise add acylating agent, stir for 1 hour, then slowly dropwise add 1-methylnaphthalene, and after the dropwise addition is complete, slowly return to room temperature and react for 0.5 hours; after the reaction is complete, pour the reaction solution into ice water and separate the phases; wash the organic phase with water to obtain the intermediate 4-acetyl-1-methylnaphthalene;

[0019] The reaction route of step (1) is as follows: ;

[0020] (2) First, add a small amount of solvent to the reaction container, and then add catalyst 1, catalyst 2, and intermediate 4-acetyl-1-methylnaphthalene in sequence; add 30% hydrogen peroxide dropwise at a slow rate, maintain the temperature at 30±5°C, and control the rate of addition over 1 hour; after the addition is completed, heat to 120°C and react for 3 hours, then quench the reaction solution; extract and crystallize to obtain 4-acetyl-1-naphthoic acid.

[0021] The reaction route of step (2) is as follows: .

[0022] In the above-mentioned method for synthesizing 4-acetyl-1-naphthoic acid, the solvent in step (1) is one of dichloromethane, chloroform, carbon disulfide, etc.

[0023] The catalyst in step (1) is one of aluminum chloride, ferric chloride and zinc chloride.

[0024] The acylating agent in step (1) is one of acetyl chloride, acetic anhydride and acetic acid.

[0025] The solvent in step (2) is one of DMF, DMSO and n-butanol.

[0026] The catalyst 1 in step (2) is one of N-hydroxyphthalimide and N,N,N-trihydroxyisocyanuric acid.

[0027] The catalyst 2 in step (2) is one of cobalt acetate and manganese acetate.

[0028] The quenching reagent (for quenching excess hydrogen peroxide) in step (2) is one of sodium thiosulfate and sodium bisulfite.

[0029] In the technical solution of the present invention, the 30% hydrogen peroxide is hydrogen peroxide with a mass percentage concentration of 30%.

[0030] Beneficial technical effects:

[0031] Compared with other synthesis methods, the synthesis method of 4-acetyl-1-naphthoic acid of the present invention has fewer steps, simple operation, low requirements on equipment, and the reagents used are relatively friendly; it avoids the use of highly toxic cyanide and the risk of high-temperature equipment, and is environmentally friendly; the single-step yield is close to 90%, the comprehensive yield reaches more than 80%, and the purity of the obtained 4-acetyl 1-naphthoic acid exceeds 99%. DETAILED DESCRIPTION

[0032] The present invention will be further described below in conjunction with specific implementation modes so that those skilled in the art can better understand the present invention, but the present invention is not limited thereto. Example 1

[0033] Synthesis of 4-acetyl-1-methylnaphthalene:

[0034] Add 50ml of dichloromethane to a 100ml three-necked flask and cool to 0℃; add 26.7g (0.2mol) of aluminum chloride; slowly drop 15.7g (0.2mol) of acetyl chloride; after stirring for 1h, slowly drop 14.2g (0.1mol) of 1-methylnaphthalene, slowly return to room temperature and react for 0.5 hours; after the reaction is complete, slowly pour the reaction solution into 40ml of ice water to quench and separate the phases; wash the organic phase with water until neutral (20ml*3), dry, and desolventize to obtain 17.2g of yellow oil with a yield of 93.5%;

[0035] Synthesis of 4-acetyl-1-naphthoic acid:

[0036] In a 100ml three-necked flask, add 20ml DMF, 1.47g (9 mol) of N-hydroxyphthalimide, 1.56g (9mol) of manganese acetate, and 17.2g (92 mmol) of 4-acetyl-1-methylnaphthalene; dilute 22.6g (0.2mol) of 30% hydrogen peroxide with 10ml DMF, slowly drip into the reaction flask, and drip completely in 1 hour; after dripping, heat to 120℃ and react for 3 hours, slowly pour the reaction solution into pre-cooled sodium sulfite solution to quench; extract with 20ml*3 of ethyl acetate, dry, desolventize to 2 times the volume, cool to 0~10℃ for crystallization, and filter to obtain 18.1g of 4-acetyl-1-naphthoic acid, with a yield of 90.5% and a purity of 98.23%. Example 2

[0037] Synthesis of 4-acetyl-1-methylnaphthalene:

[0038] Add 50ml of chloroform to a 100ml three-necked flask and cool to 0℃; add 26.7g (0.2mol) of aluminum chloride; slowly drop 20.38g (0.2mol) of acetic anhydride; after stirring for 1h, slowly drop 14.2g (0.1mol) of 1-methylnaphthalene, slowly return to room temperature and react for 0.5 hours; after the reaction is completed, slowly pour the reaction solution into 40ml of ice water to quench and separate the phases; wash the organic phase with water until neutral (20ml*3), dry, and desolventize to obtain 16.4g of light yellow oil with a yield of 89.1%;

[0039] Synthesis of 4-acetyl-1-naphthoic acid:

[0040] In a 100ml three-necked flask, add 20ml DMSO, 1.59g (9 mmol) of N,N,N-trihydroxyisocyanuric acid, 1.59g (9 mmol) of cobalt acetate, and 16.4g (88 mmol) of 4-acetyl-1-methylnaphthalene; dilute 22.6g (0.2mol) of 30% hydrogen peroxide with 10ml DMSO, and slowly drip into the reaction flask, and drip completely in 1 hour; after dripping, heat to 120℃ and react for 3 hours, and slowly pour the reaction solution into pre-cooled sodium sulfite solution to quench; extract with 20ml*3 of ethyl acetate, dry, desolventize to 2 times the volume, cool to 0~10℃ for crystallization, and filter to obtain 17.5g of 4-acetyl-1-naphthoic acid, with a yield of 91.8% and a purity of 99.34%. Example 3

[0041] Synthesis of 4-acetyl-1-methylnaphthalene:

[0042] Add 100ml of dichloromethane to a 100ml three-necked flask and cool to 0℃; add 40.9g (0.3mol) of zinc chloride; slowly drop 23.5g (0.105mol) of acetyl chloride; after stirring for 1h, slowly drop 14.2g (0.1mol) of 1-methylnaphthalene, slowly return to room temperature and react for 0.5 hours; after the reaction is completed, slowly pour the reaction solution into 40ml of ice water to quench and separate the phases; wash the organic phase with water until neutral (20ml*3), dry, and desolventize to obtain 16.8g of light yellow oil with a yield of 91.3%;

[0043] Synthesis of 2-methyl-4-acetylbenzoic acid:

[0044] In a 100ml three-necked flask, add 20ml of n-butanol, 1.59g (9mmol) of N,N,N-trihydroxyisocyanuric acid, 1.56g (9mmol) of manganese acetate, and 16.8g (90mmol) of 4-acetyl-1-methylnaphthalene; dilute 22.6g (0.2mol) of 30% hydrogen peroxide with 10ml of n-butanol, slowly drip into the reaction flask, and drip completely in 1 hour; after dripping, heat to 120℃ and react for 3 hours, slowly pour the reaction solution into precooled sodium sulfite solution to quench; concentrate under reduced pressure to recover n-butanol, extract with 20ml*3 of ethyl acetate, dry, desolventize, cool to 0~10℃ for crystallization, and filter to obtain 17.6g of 4-acetyl-1-naphthoic acid with a yield of 90.1% and a purity of 99.1%.

Claims

1. A method for synthesizing 4-acetyl-1-naphthoic acid, characterized in that: The steps include: (1) Add solvent to the reaction vessel, cool to below 0°C, add catalyst, dropwise add acylating agent, stir for 1 hour, then dropwise add 1-methylnaphthalene, after the addition is complete, return to room temperature and react for 0.5 hour; after the reaction is complete, pour the reaction solution into ice water to quench, separate the phases; wash the organic phase with water to obtain the intermediate 4-acetyl-1-methylnaphthalene; (2) First, add a solvent to a reaction vessel, and then add catalyst 1, catalyst 2, and intermediate 4-acetyl-1-methylnaphthalene in sequence; add 30% hydrogen peroxide dropwise at a slow rate, maintain the temperature at 30±5°C, and control the rate to complete the dropwise addition within 1 hour; after the dropwise addition is completed, heat the temperature to 120°C and react for 3 hours, then quench the reaction solution; extract and crystallize to obtain 4-acetyl-1-naphthoic acid; The solvent in step (1) is one of dichloromethane, chloroform and carbon disulfide; The catalyst in step (1) is one of aluminum chloride, ferric chloride and zinc chloride; The acylating agent in step (1) is one of acetyl chloride, acetic anhydride and acetic acid; The solvent in step (2) is one of DMF, DMSO and n-butanol; The catalyst 1 in step (2) is N,N,N-trihydroxyisocyanuric acid; The catalyst 2 in step (2) is one of cobalt acetate and manganese acetate.

2. The synthetic method of 4-acetyl-1-naphthoic acid according to claim 1, characterized in that, The quenching reagent used in the step of quenching the reaction solution in step (2) is one of sodium thiosulfate and sodium bisulfite.

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