Method for preparing musk ketone

Abstract

The invention relates to the field of chemical production, and discloses a method for preparing musk ketone. The product is obtained by preparing the p-tert-butyl-2, 6-dimethyl bromobenzene, then preparing the acylate, preparing the nitride and finally recrystallizing and purifying, and compared with the original process, the method has the advantages that the cost is saved by nearly half, and few hazardous wastes are generated. When the p-tert-butyl-2, 6-dimethyl bromobenzene is prepared, the 2, 6-dimethyl bromobenzene is directly reacted with the tert-butyl alcohol to synthesize the p-tert-butyl-2, 6-dimethyl bromobenzene, and the traditional Friedel-Crafts alkylation reaction is not adopted, so that the generation of wastewater and waste gas is reduced, and energy conservation and emission reduction are realized. When the acylate is prepared, a coupling reaction is adopted, so that acetic anhydride with high harmfulness is prevented from being used as an acylating agent, the generation of wastewater is reduced, and the method is environment-friendly. The solvent is added in the nitration reaction, so that the risk of the reaction is reduced to the minimum. In the nitration process, a large amount of musk xylene and standard nitrates can be generated in the original process. In the subsequent purification process, the musk xylene and the musk ketone are basically consistent in property, so that the musk xylene and the standard nitride cannot be controlled in a standard range in the purification process. The nitration reaction is carried out by dropwise adding nitric acid and adding a small amount of acetic anhydride. According to the dropwise adding mode, the musk xylene in the reaction process can be controlled to be within the specified range of the national standard, and the impurity does not need to be purified in a targeted mode in the subsequent purification process. And the reaction time is shortened by about half compared with the original process. And the purified mother liquor can be concentrated and further purified to serve as a byproduct, so that the comprehensive benefits of enterprises are improved.

Description

Technical Field

[0001] This invention belongs to the field of fine chemicals and relates to the production of musk, specifically to a method for preparing ketone musk. Background Technology

[0002] Ketone musk is a synthetic musk used in the formulation of fragrances. Its aroma is more elegant than xylene musk, and it is used as a fixative; in the formulation of cosmetic and soap fragrances; it can also be used in combination with methyl violet copper, cinnamyl alcohol, benzyl salicylate, and other fragrances to formulate powdered fragrances.

[0003] Existing production methods are complex, leave many residues, and contain high levels of xylene and musk, which cannot be completely removed. Furthermore, they require sophisticated equipment. Therefore, a production method that is easy to operate, has a high safety factor, is low in cost, and has a high conversion rate is needed.

[0004] Currently, the production of ketone musk mainly involves Friedel-Crafts alkylation, Friedel-Crafts acylation, and nitration reactions of m-xylene. For example, CN 113024381 discloses a method for synthesizing ketone musk by starting with tert-butanol to prepare tert-chlorobutane, then Friedel-Crafts alkylation with m-xylene, followed by Friedel-Crafts acylation with acetic anhydride, and finally nitration. This method involves two Friedel-Crafts reactions, uses a large amount of catalyst, and generates a large amount of waste acid water during post-treatment. Furthermore, the addition of acetic anhydride during acylation deactivates the catalyst, resulting in low reaction yield. Additionally, the excessive amount of raw materials during nitration leads to an excessively high xylene-musk content in the final product, increasing the difficulty of post-treatment.

[0005] CN 114671765 discloses a method for preparing ketone musk from acylates. This method uses a mixed acid mode of nitric acid and sulfuric acid for nitration. This method ultimately generates a large amount of waste mixed acid, which increases the difficulty of treatment and the environmental pressure. Moreover, the nitration of ketone musk needs to be carried out at low temperature, otherwise a large amount of local nitration products and xylene musk will be generated, ultimately resulting in low conversion rate and low product yield.

[0006] Summary of the Invention

[0007] To address the problems of the prior art, this invention provides a method for preparing ketone musk, which has the advantages of using inexpensive and readily available raw materials with stable chemical properties, simple and continuous operation, minimal waste generation, and recyclable solvents that require only simple treatment for reuse. It is also environmentally friendly. Each reaction step is thorough, resulting in high conversion rates and yielding ketone musk in good condition with high content.

[0008] This invention is achieved through the following technical solution: Preparation of p-tert-butyl-2,6-dimethylbromobenzene: Metered amounts of 2,6-dimethylbromobenzene and ferric chloride were added to a reactor, and stirring was started while controlling the reactor temperature. Tert-butanol was then added dropwise to the reactor, controlling the addition time. After the addition was complete, the temperature was raised to a specified level, and the mixture was stirred and maintained at this temperature for 1 hour. Sodium carbonate solution was then added to the reaction system, the temperature was raised to 80°C, and the mixture was stirred for 1 hour. Stirring was then stopped, and the mixture was allowed to stand for 30 minutes. The upper layer of product was transferred to a finished product storage tank, and the lower layer of wastewater was transferred to a wastewater storage tank. The molar ratio of 2,6-dimethylbromobenzene:ferric chloride:tert-butanol was 1:0.5:1.

[0009] Synthesis of 4-tert-butyl-2,6-dimethylacetophenone: Under nitrogen protection, the measured amounts of the previous step product, organotin compound, Pd(OAc)₂, DPPF, triethylamine, and tetrabutylammonium bromide were added to the reactor, and the mixture was evacuated and purged with nitrogen three times. N,N-dimethylformamide was added to the reactor, and the reaction was heated. After cooling to room temperature and monitoring by TLC, water and a small amount of acetic acid were added, followed by extraction with dichloromethane. The dichloromethane was removed by rotary evaporation, and the product was obtained by vacuum distillation. The molar ratio of catalyst, ligand, and previous step product was 1:2:10; the molar ratio of previous step product, organotin compound, and base was 1:1.2:1.2; and the molar ratio of additive to previous step product was 0.1:5.

[0010] Synthesis of ketone musk: The product from the previous step was added to a reaction vessel, and a measured amount of 1,2-dichloroethane was added to the vessel with stirring. The refrigerated brine was turned on to cool the vessel. Acetic anhydride was added to the vessel, and concentrated nitric acid was added dropwise. After the addition was complete, the vessel was kept warm and stirred until the reaction was complete. The product ketone musk was obtained after post-treatment. The molar ratio of the product from the previous step, concentrated nitric acid, and acetic anhydride was 1:11:0.2.

[0011] In step 1), the tert-butanol was added at a temperature of 20°C for 1 hour and at a reaction temperature of 45°C.

[0012] In step 2), the reaction temperature is 140℃ and the reaction time is 15h.

[0013] In step 3), the dropping temperature is -10℃; the reaction temperature is -5℃; and the reaction time is 8 hours.

[0014] The post-processing method in step 3) is extraction, concentration, and recrystallization; the solvent used for extraction is 1,2-dichloroethane, the amount of solvent used is the reaction solution, the solvent volume ratio is 1:0.5, and the number of extractions is 2.

[0015] In step 3), the solvent used for post-treatment recrystallization is any one of methanol, ethanol, or ethyl acetate, preferably ethanol; the amount of solvent used is 3-5 times the mass of the concentrated crude product, preferably 3 times.

[0016] The post-treatment method in step 3) is to add 3 times the mass of ethanol, stir and heat until completely dissolved, turn off the heating and cool down to 20-30℃, filter, rinse with 1 times the mass of ethanol, and dry to obtain pure ketone musk.

[0017] The main advantages of this invention are: 1. The present invention reduces the number of steps and saves on raw material costs.

[0018] 2. This invention uses the direct reaction of 2,6-dimethylbromobenzene and tert-butanol to synthesize 5-tert-butyl-2,6-dimethylbromobenzene, avoiding the use of Friedel-Crafts alkylation, reducing waste gas generation, and is environmentally friendly.

[0019] 3. This invention uses a coupling reaction to synthesize acylates, avoiding the use of acetic anhydride, thus increasing the reaction conversion rate and reducing waste.

[0020] 4. The present invention uses the method of adding concentrated nitric acid dropwise to the reaction system to control the generation of the impurity xylene and musk.

[0021] 5. In this invention, acetic anhydride is added to the reaction system during nitration, which can control the formation of its native nitrate and improve the raw material conversion rate and product yield. Specific Implementation

[0022] The present invention will be described in detail below through embodiments, but the present invention is not limited to the following embodiments. Example

[0023] Preparation of p-tert-butyl-2,6-dimethylbromobenzene Add 185g of 2,6-dimethylbromobenzene and 81g of ferric chloride to the reactor, start stirring, and control the temperature inside the reactor. Begin adding 74g of tert-butanol dropwise to the reactor, controlling the dropping time to 1 hour. After the addition is complete, raise the temperature to 45°C, maintain this temperature and stir for 1 hour. Add sodium carbonate solution to the reactor, raise the temperature to 80°C, maintain this temperature and stir for 1 hour, then turn off the stirring and let it stand for 30 minutes. Transfer the upper layer of product to the finished product storage tank, and transfer the lower layer of wastewater to the wastewater storage tank, obtaining 224g of product with a purity of 99%.

[0024] Preparation of 4-tert-butyl-2,6-dimethylacetophenone Under nitrogen protection, 168.7 g of the product from the previous step, 280 g of an organotin compound, 15.72 g of Pd(OAc)₂, 77.56 g of DPPF, 84.84 g of triethylamine, and 3.37 g of tetrabutylammonium bromide were added to the reactor, and the mixture was evacuated and purged with nitrogen three times. 400 g of N,N-dimethylformamide was then added to the reactor, and the reaction was heated. After cooling to room temperature and monitoring by TLC, water and a small amount of acetic acid were added, followed by extraction with dichloromethane. The dichloromethane was removed by rotary evaporation, and the product was purified by vacuum distillation to obtain 128 g of product with a purity of 99%.

[0025] Preparation of Ketone Musk Add 140g of the product from the previous step to the reaction vessel, start stirring and add 200g of 1,2-dichloroethane. Turn on the freezing brine and cool to -10℃. Add 14g of acetic anhydride to the vessel and start adding 485g of concentrated nitric acid dropwise, controlling the dropping temperature at around -5℃ for 3 hours. After the addition is complete, keep at -5℃ and stir until the reaction is complete. Slowly pour the reaction solution into 1000g of ice water and stir for 30 minutes. Let it stand to separate into layers. Extract the upper acidic water once with 500ml of dichloroethane. Combine the organic phases, remove the solvent by vacuum distillation, and heat with 600g of ethanol under reflux until completely dissolved. Cool to 0℃ and filter to obtain 157.37g of pure ketone musk with a content greater than 99%, as a white powder, containing 0.01% xylene musk. Example

[0026] Preparation of p-tert-butyl-2,6-dimethylbromobenzene Add 185g of 2,6-dimethylbromobenzene and 51g of aluminum trichloride to the reactor, start stirring, and control the temperature inside the reactor. Begin adding 74g of tert-butanol dropwise to the reactor, controlling the dropping time to 1 hour. After the addition is complete, raise the temperature to 45°C, maintain this temperature and stir for 1 hour. Add sodium carbonate solution to the reactor, raise the temperature to 80°C, maintain this temperature and stir for 1 hour, then turn off the stirring and let it stand for 30 minutes. Transfer the upper layer of product to the finished product storage tank, and transfer the lower layer of wastewater to the wastewater storage tank, obtaining 126g of product with a purity of 99%.

[0027] Preparation of 4-tert-butyl-2,6-dimethylacetophenone Under nitrogen protection, 168.7 g of the previous product, 280 g of organotin compound, 15.72 g of Pd(OAc)₂, 77.56 g of DPPF, 62.1 g of potassium carbonate, and 3.37 g of tetrabutylammonium bromide were added to the reactor, and the mixture was evacuated and purged with nitrogen three times. 400 g of N,N-dimethylformamide was added to the reactor, and the reaction was heated. After cooling to room temperature, the mixture was monitored by TLC. Water and a small amount of acetic acid were added, followed by extraction with dichloromethane. The dichloromethane was removed by rotary evaporation, and the product was purified by vacuum distillation to obtain 127.3 g of product with a purity of 99%.

[0028] Preparation of Ketone Musk Add 140g of the product from the previous step to the reaction vessel, start stirring and add 200g of 1,2-dichloroethane. Turn on the freezing brine and cool to -10℃. Add 14g of acetic anhydride to the vessel and start adding 485g of concentrated nitric acid dropwise, controlling the dropping temperature at around -5℃ for 3 hours. After the addition is complete, keep at -5℃ and stir until the reaction is complete. Slowly pour the reaction solution into 1000g of ice water and stir for 30 minutes. Let it stand to separate into layers. Extract the upper acidic water once with 500ml of dichloroethane. Combine the organic phases, remove the solvent by vacuum distillation, and heat to reflux with 600g of ethanol until completely dissolved. Cool to 0℃ and filter to obtain 155.85g of pure ketone musk with a content greater than 99%, as a white powder, containing 0.05% xylene musk.

[0029] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A method for preparing ketone musk, characterized in that... The specific steps are as follows: Preparation of p-tert-butyl-2,6-dimethylbromobenzene: A measured amount of 2,6-dimethylbromobenzene and acid were added to a reaction vessel, and stirring was started while controlling the temperature inside the vessel. Tert-butanol was then added dropwise to the reaction vessel, controlling the addition time. After the addition was complete, the temperature was raised to a specified level, and the mixture was stirred and maintained at this temperature for 1 hour. Sodium carbonate solution was then added to the reaction system, the temperature was raised to 80°C, and the mixture was stirred for 1 hour. Stirring was then stopped, and the mixture was allowed to stand for 30 minutes. The upper layer of product was transferred to a finished product storage tank, and the lower layer of wastewater was transferred to a wastewater storage tank. Synthesis of 4-tert-butyl-2,6-dimethylacetophenone: Under nitrogen protection, the measured product from the previous step, organotin compound, catalyst, ligand, base, and additives were added to the reactor, and the reactor was evacuated and purged with nitrogen three times. Solvent was added to the reactor, and the reaction was heated. After cooling to room temperature and monitoring by TLC, water and a small amount of acetic acid were added, followed by solvent extraction, solvent removal by rotary evaporation, and vacuum distillation to obtain the product. Ketone musk synthesis: The product from the previous step was added to a reaction vessel, the stirring was turned on, the measured amount of solvent was added to the vessel, the freezing brine was turned on, the temperature was lowered, acetic anhydride was added to the vessel, concentrated nitric acid was added dropwise, after the addition was completed, the temperature was maintained and stirred until the reaction was complete, and the finished ketone musk was obtained after post-treatment.

2. The method for preparing ketone musk according to claim 1, characterized in that, include: In step A, the acid is an inorganic acid or a Lewis acid, selected from hydrochloric acid, ferric chloride, and aluminum chloride, preferably ferric chloride; In step B, the catalyst is any one of Pd(acac)2, Pd(OAc)2, PdCl2, Pd(PPh3)2Cl2, Pd(dppf)Cl2, Pd2(dba)3, Pd(TFA)2, Pd2(allyl)2Cl2, Ni(COD)2, and NiCl2(PCy3)2, preferably Pd(OAc)2; In step B, the ligand is any one of BrettPhos, SPhos, IPr, IMes, SIMes, XPhos, RuPhos, PtBu3, DPPF, and BINAP, preferably DPPF. The base in step B is any one of potassium phosphate trihydrate, anhydrous potassium phosphate, potassium carbonate, cesium carbonate, potassium acetate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, potassium hydroxide, or triethylamine, preferably triethylamine; In step B, the additive is tetrabutylammonium bromide, tris(3,6-dioxaneheptyl)amine or 18-crown-6, preferably tetrabutylammonium bromide; In step B, the solvent is any one of 1,2-dichloroethane, dioxane, toluene, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, methyl tert-butyl ether, n-heptane, isopropanol, or ethylene glycol dimethyl ether, preferably N,N-dimethylformamide. In step C, the solvent is any one of 1,2-dichloroethane, dichloromethane, ethyl acetate, chloroform, and toluene, preferably 1,2-dichloroethane.

3. The method for preparing ketone musk according to claims 1-2, characterized in that, include: In step A, the molar ratio of 2,6-dimethylbromobenzene:ferric chloride:tert-butanol is 1:0.2:1-1.5, preferably 1:0.5:1; In step B: the molar ratio of catalyst, ligand and product from the previous step is 1:(1-10):(5-100), preferably 1:2:10; the molar ratio of product from the previous step, organotin compound and base is 1:(1-5):(1-10), preferably 1:1.2:1.2; and the molar ratio of additive to product from the previous step is (0.1-1):5, preferably 0.1:

5. In step C, the molar ratio of the product from the previous step, concentrated nitric acid, and acetic anhydride is 1:(8-12):(0.1-1), preferably 1:11:0.

2.

4. The method for preparing ketone musk according to claims 1-3, characterized in that, include: In step A, the dropping temperature of tert-butanol is 0-35℃, preferably 20℃; the dropping time is 0.5-1.5h, preferably 1h; and the reaction temperature is 20-50℃, preferably 45℃. In step B, the reaction temperature is 80-160℃, preferably 140℃, and the reaction time is 6-20h, preferably 15h. In step C, the dropping temperature is 0~-18℃, preferably -10℃; the reaction temperature is 10~-15℃, preferably -5℃; and the reaction time is 4~15h, preferably 8h.

5. The method for preparing ketone musk according to claims 1-4, characterized in that, include: The post-processing method in step A is to allow the wastewater to settle and separate into layers, with the lower layer of wastewater entering a wastewater storage tank and the upper layer of product entering a product storage tank for later use. The post-processing method of step B is to add water and a small amount of acetic acid for hydrolysis, solvent extraction, solvent removal by rotary evaporation, and vacuum distillation to obtain the product. The post-processing method of step C is to pour the reaction solution into ice water for hydrolysis, allow it to stand and separate into layers, extract with solvent, remove the solvent by rotation, and recrystallize to obtain the product.

6. The method for preparing ketone musk according to claims 1-5, characterized in that, include: In step B, the extraction solvent is any one of dichloromethane, 1,2-dichloroethane, ethyl acetate, and petroleum ether, preferably dichloromethane. The extraction solvent in step C is one of dichloromethane, dichloroethane, ethyl acetate, and petroleum ether, preferably 1,2-dichloroethane.

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