Preparation method of aromatic brominated compound
By using cystine or cysteine as catalysts, combining N-bromosuccinimide and acetonitrile solvent, the problem of difficulty in introducing bromine atoms on aromatic rings in the prior art is solved, and high efficiency and low toxicity are achieved. Environmentally friendly preparation of 3-bromo-4-methoxybenyl compounds.
Patent Information
- Application Number
- CN202411430501.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-14
- Publication Date
- 2025-01-14
AI Technical Summary
The prior art is difficult to control the reaction conditions when introducing bromine atoms onto the aromatic ring, especially when there are electron-absorbing groups, and the commonly used catalyst diphenyl sulfide is toxic and affects environmental friendliness.
Cystine or cysteine is used as catalyst, combined with N-bromosuccinimide and acetonitrile solvent, and under the protection of inert gas, the reaction is carried out to introduce bromine atoms, control the reaction conditions to improve the introduction position of bromine atoms and Quantity controllability.
The preparation of 3-bromo-4-methoxybenyl compounds with high yield and purity is achieved, with low catalyst toxicity, environmentally friendly, easy to control reaction conditions and low cost.
Smart Images
Figure CN119306597A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the field of chemical synthesis, and in particular relates to a method for preparing an aromatic bromine compound having a structure of formula (I).
[0002] Background Art
[0003] 3-bromo-4-methoxybenzoyl compounds, such as methyl 3-bromo-4-methoxybenzoate, ethyl 3-bromo-4-methoxybenzoate or 3-bromo-4-methoxyacetophenone, are a class of chemicals with a wide range of uses and can be used in the fields of medicine, pesticides and spices. In the field of pesticides, methyl 3-bromo-4-methoxybenzoate and ethyl 3-bromo-4-methoxybenzoate can inhibit grain spotting, and can also be used to prepare herbicides, sterilizers, etc. They can also be used as intermediates to prepare liquid crystal materials, drugs, etc., and have a wide range of uses. 3-bromo-4-methoxyacetophenone is also an important class of drug intermediates.
[0004] In the prior art, the introduction of bromine atoms on aromatic groups can be achieved by brominating the corresponding aromatic rings with NBS. In the technology of brominating benzene rings with NBS, AIBN (2-benzhydryl-2-azabicyclo [3.2.1] heptane), BPO (dibenzoyl peroxide) and the like are usually used as catalysts or initiators, but it is usually necessary to strictly control the temperature or light conditions, otherwise the bromine atoms cannot be introduced according to the expected position and quantity, and the difficulty of post-processing is increased. When there are electron-withdrawing groups (such as ester groups, carbonyl groups, etc.) on the aromatic rings, it becomes extremely difficult to access bromine atoms on the aromatic rings. Although the prior art can use diphenyl sulfide as a catalyst to introduce bromine atoms on aromatic rings connected with electron-withdrawing groups, diphenyl sulfide is generally considered to be toxic and can be absorbed by ingestion, inhalation or skin contact. Diphenyl sulfide may cause serious harm or even death. In addition, diphenyl sulfide is extremely toxic to aquatic organisms and may have long-term adverse effects on the aquatic environment.
[0005] The art needs to seek a catalyst that can access bromine on an aromatic ring when an electron-withdrawing group is present on the aromatic ring (such as a benzene ring), the catalyst has low toxicity, is environmentally friendly, and the reaction conditions of the method are easy to control, and a method for preparing 3-bromo-4-methoxybenzoyl compounds with high yield and purity is provided. Summary of the invention
[0006] In view of the deficiencies in the prior art, one of the purposes of the present invention is to provide a method for preparing an aromatic brominated compound having a structure of formula (I).
[0007]
[0008] The preparation method comprises the following steps:
[0009] (1) using acetonitrile as a solvent, mixing a first raw material and N-bromosuccinimide, adding cystine and / or cysteine as a catalyst, stirring and reacting under the protection of an inert gas to obtain a reaction solution;
[0010] The first raw material has a structure of formula (II):
[0011]
[0012] In formula (I) and formula (II), R1 is selected from any one of methyl, ethoxy and methoxy;
[0013] (2) After post-treatment of the reaction solution, a compound of formula (I) is obtained.
[0014] When R1 is a methoxy group, formula (I) is methyl 3-bromo-4-methoxybenzoate, and formula (II) is methyl p-methoxybenzoate; when R1 is an ethoxy group, formula (I) is ethyl 3-bromo-4-methoxybenzoate, and formula (II) is ethyl p-methoxybenzoate; when R1 is a methyl group, formula (I) is 3-bromo-4-methoxyacetophenone, and formula (II) is p-methoxyacetophenone.
[0015] The invention selects cystine or cysteine as a catalyst (and / or initiator) to catalyze or initiate a reaction of introducing bromine atoms into a specific position of a benzene ring having a strong electron-withdrawing group (such as a carbonyl group or an ester group) by NBS to synthesize a compound of formula (I). The introduction position and the introduction amount of the bromine atoms are well controllable, the product yield and purity are high, the catalyst cost is low, the reaction conditions are mild, and the controllability is good. In addition, cystine and cysteine are environmentally friendly, low-toxic, and free of odor.
[0016] The inert gas protection exemplarily includes nitrogen protection, argon protection or helium protection, preferably nitrogen protection.
[0017] Preferably, the catalyst is calculated based on cysteine, and the molar ratio of the catalyst to the first raw material is 0.2:1 to 0.6:1, such as 0.3:1, 0.4:1, 0.5:1, etc.
[0018] Preferably, when the catalyst is cysteine, the molar ratio of the catalyst to the first raw material is 0.4:1 to 0.6:1; when the catalyst is cystine, the molar ratio of the catalyst to the first raw material is 0.2:1 to 0.3:1.
[0019] Preferably, the molar ratio of the first raw material to N-bromosuccinimide is 1:2.5 to 1:4.0, for example, 1:2.7, 1:2.9, 1:3.2, 1:3.4, etc.
[0020] Preferably, the amount of acetonitrile added is 15 to 25 times the mass of the first raw material, for example, 16 times, 18 times, 19 times, 20 times, 21 times, 23 times, 24 times, etc.
[0021] Preferably, the catalyst is cysteine.
[0022] Using cysteine as a catalyst has lower cost and stronger reaction activity, and can shorten the reaction time to a certain extent compared to cystine.
[0023] Preferably, the reaction temperature is 25-35°C, such as 26°C, 28°C, 30°C, 33°C, etc., and the reaction time is 12-24h, such as 13h, 16h, 19h, 22h, etc., preferably 18-22h.
[0024] The reaction time of the present application is preferably 18 to 22 hours, and the molar yield of the product can reach more than 90%.
[0025] Preferably, the post-treatment in step (2) comprises neutralizing and removing bromine from the reaction solution, extracting, washing, drying, and concentrating the organic phase to obtain methyl 3-bromo-4-methoxybenzoate.
[0026] Preferably, the neutralizing agent is sodium carbonate; and the debromination agent is sodium thiosulfate.
[0027] Preferably, the neutralization and debromination steps include using a mixed solution of a saturated sodium carbonate solution and a saturated sodium thiosulfate solution in a volume ratio of 1:1.
[0028] Preferably, the extraction solvent is ethyl acetate.
[0029] The second purpose of the present application is to provide a use of cystine, wherein the cystine is used as a catalyst for synthesizing the compound of formula (I) using the compound of formula (II) and NBS as raw materials.
[0030] Preferably, the cystine comprises L-cystine and / or R-cystine.
[0031] The third object of the present application is to provide a use of cysteine, wherein the cysteine is used as a catalyst for synthesizing a compound of formula (I) using formula (II) and NBS as raw materials;
[0032] Preferably, the cystine comprises L-cysteine and / or R-cysteine.
[0033] Compared with the prior art, this application has the following beneficial effects:
[0034] (1) The present invention uses cystine or cysteine as a catalyst (and / or initiator) to catalyze or initiate the reaction of introducing bromine atoms at specific positions of the benzene ring by NBS to synthesize the compound of formula (I). The position and amount of the bromine atoms introduced are well controllable, the product yield and purity are high, the catalyst cost is low, the reaction conditions are mild, and the controllability is good.
[0035] (2) The present invention provides a new use of cystine and / or cysteine. BRIEF DESCRIPTION OF THE DRAWINGS
[0036] Figure 1 The gas chromatogram of the product methyl 3-bromo-4-methoxybenzoate is given;
[0037] Figure 2 The NMR of the product methyl 3-bromo-4-methoxybenzoate is given. DETAILED DESCRIPTION
[0038] The technical solution of the present invention is further explained below in conjunction with specific implementation methods. However, it should be noted that the specific implementation methods are only a specific implementation and explanation of the essence of the technical solution of the present invention, and should not be understood as a limitation on the protection scope of the present invention.
[0039] The reagents and instruments used in the examples can all be purchased from commercial products, and the detection methods are conventional methods well known in the art.
[0040] Example 1
[0041] A method for preparing methyl 3-bromo-4-methoxybenzoate comprises the following steps:
[0042] (1) Under nitrogen atmosphere, 3.323 g (0.02 mol) of methyl 4-methoxybenzoate was added to a 250 mL reaction container, 1.21 g (0.01 mol) of L-cysteine as a catalyst was added to 75 mL of acetonitrile as a solvent, and 10.68 g of NBS (0.06 mol) was added, and the reaction mixture was stirred at room temperature for 18 h to obtain a reaction solution;
[0043] (2) A mixed solution of a saturated sodium carbonate solution and a saturated sodium thiosulfate solution in a volume ratio of 1:1 was added to the reaction solution, followed by extraction with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain 4.92 g of methyl 3-bromo-4-methoxybenzoate product with a purity of 98% and a calculated molar yield of 98%.
[0044] Figure 1 The gas chromatogram of methyl 3-bromo-4-methoxybenzoate product is given. After normalization calculation, the purity is 98%;
[0045] Figure 2 The NMR of the product 3-bromo-4-methoxybenzoic acid methyl ester is given. Figure 2 The nuclear magnetic resonance results are H-NMR (solvent: deuterated chloroform), chemical shifts: 8,27, s, 1H; 8.01, d, 1H; 6.94, d, 1H; 3.99, s, 3H; 3.93, s, 3H, which are consistent with the analytical results of methyl 3-bromo-4-methoxybenzoate.
[0046] Example 2
[0047] A method for preparing methyl 3-bromo-4-methoxybenzoate comprises the following steps:
[0048] (1) Under nitrogen atmosphere, 3.323 g (0.02 mol) of methyl 4-methoxybenzoate was added to a 250 mL reaction container, 1.45 g (0.012 mol) of L-cysteine as a catalyst was added to 80 mL of acetonitrile as a solvent, and 14.24 g of NBS (0.08 mol) was added, and the reaction mixture was stirred at room temperature for 24 h to obtain a reaction solution;
[0049] (2) A mixed solution of a saturated sodium carbonate solution and a saturated sodium thiosulfate solution in a volume ratio of 1:1 was added to the reaction solution, followed by extraction with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain 4.91 g of methyl 3-bromo-4-methoxybenzoate product with a purity of 98% and a calculated molar yield of 99%.
[0050] Example 3
[0051] A method for preparing methyl 3-bromo-4-methoxybenzoate comprises the following steps:
[0052] (1) Under nitrogen atmosphere, 3.323 g (0.02 mol) of methyl 4-methoxybenzoate was added to a 250 mL reaction container, 1.02 g (0.042 mol) of catalyst cysteine was added to 100 mL of solvent acetonitrile, and 14.22 g of NBS (0.08 mol) was added, and the reaction mixture was stirred at room temperature for 24 hours to obtain a reaction solution;
[0053] (2) A mixed solution of a saturated sodium carbonate solution and a saturated sodium thiosulfate solution in a volume ratio of 1:1 was added to the reaction solution, followed by extraction with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain 4.78 g of methyl 3-bromo-4-methoxybenzoate product with a purity of 97% and a calculated molar yield of 94%.
[0054] Example 4
[0055] A method for preparing ethyl 3-bromo-4-methoxybenzoate comprises the following steps:
[0056] (1) Under nitrogen atmosphere, 3.534 g (0.02 mol) of ethyl 4-methoxybenzoate was added to a 250 mL reaction container, 1.22 g (0.01 mol) of L-cysteine as a catalyst was added to 70 mL of acetonitrile as a solvent, and 10.72 g (0.06 mol) of NBS was added, and the reaction mixture was stirred at room temperature for 18 h to obtain a reaction solution;
[0057] (2) A mixed solution of a saturated sodium carbonate solution and a saturated sodium thiosulfate solution in a volume ratio of 1:1 was added to the reaction solution, followed by extraction with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain 4.97 g of methyl 3-bromo-4-methoxybenzoate product with a purity of 99% and a calculated molar yield of 97%.
[0058] Example 5
[0059] A method for preparing 3-bromo-4-methoxyacetophenone comprises the following steps:
[0060] (1) Under nitrogen atmosphere, 3.038 g (0.02 mol) of 4-methoxyacetophenone was added to 80 mL of acetonitrile as a solvent, 1.25 g (0.01 mol) of L-cysteine as a catalyst, and 10.77 g (0.06 mol) of NBS were added to a 250 mL reaction container. The reaction mixture was stirred at room temperature for 18 h to obtain a reaction solution.
[0061] (2) A mixed solution of a saturated sodium carbonate solution and a saturated sodium thiosulfate solution in a volume ratio of 1:1 was added to the reaction solution, followed by extraction with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain 4.44 g of 3-bromo-4-methoxyacetophenone product with a purity of 98% and a calculated molar yield of 94%.
[0062] Comparative Example 1
[0063] A method for preparing methyl 3-bromo-4-methoxybenzoate comprises the following steps:
[0064] (1) Under a nitrogen atmosphere, 3.325 g (0.02 mol) of methyl 4-methoxybenzoate was added to a 250 mL reaction container, 1.86 g (0.01 mol) of diphenyl sulfide as a catalyst was added to 75 mL of acetonitrile as a solvent, and 10.75 g of NBS (0.06 mol) was added, and the reaction mixture was stirred at room temperature for 18 hours to obtain a reaction solution;
[0065] (2) A mixed solution of a saturated sodium carbonate solution and a saturated sodium thiosulfate solution in a volume ratio of 1:1 was added to the reaction solution, followed by extraction with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain 4.66 g of methyl 3-bromo-4-methoxybenzoate product with a purity of 98% and a calculated molar yield of 93%.
[0066] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.
Claims
1. A method for preparing an aromatic brominated compound having a structure of formula (I), characterized in that: The preparation method comprises the following steps: (1) using acetonitrile as a solvent, mixing a first raw material and N-bromosuccinimide, adding cystine and / or cysteine as a catalyst, stirring and reacting under the protection of an inert gas to obtain a reaction solution; The first raw material has a structure of formula (II): In formula (I) and formula (II), R1 is selected from any one of methyl, ethoxy and methoxy; (2) After post-treatment of the reaction solution, a compound of formula (I) is obtained.
2. The preparation method according to claim 1, characterized in that The catalyst is calculated based on cysteine, and the molar ratio of the catalyst to the first raw material is 0.2:1 to 0.6:
1.
3. The preparation method according to any one of claims 1 to 2, characterized in that: The molar ratio of the first raw material to N-bromosuccinimide is 1:2.5 to 1:4.
0.
4. The preparation method according to any one of claims 1 to 3, characterized in that: The amount of acetonitrile added is 15 to 25 times the mass of the first raw material.
5. The preparation method according to any one of claims 1 to 4, characterized in that: The catalyst is cysteine.
6. The preparation method according to any one of claims 1 to 5, characterized in that: The reaction temperature is 25-35° C., and the reaction time is 12-24 hours.
7. The preparation method according to any one of claims 1 to 6, characterized in that: The post-treatment in step (2) comprises neutralizing and removing bromine from the reaction solution, extracting, washing and drying the organic phase, and concentrating to obtain methyl 3-bromo-4-methoxybenzoate.
8. The preparation method according to claim 7, characterized in that: The neutralizing agent is sodium carbonate; the debromination agent is sodium thiosulfate; Preferably, the neutralization and debromination step comprises using a mixed solution of a saturated sodium carbonate solution and a saturated sodium thiosulfate solution in a volume ratio of 1:1; Preferably, the extraction solvent is ethyl acetate.
9. A use of cystine, characterized in that: The cystine is used as a catalyst for synthesizing the compound of formula (I) using formula (II) and NBS as raw materials; Preferably, the cystine includes L-cystine and / or R-cystine.
10. A use of cysteine, characterized in that: The cysteine is used as a catalyst for synthesizing the compound of formula (I) using formula (II) and NBS as raw materials; Preferably, the cystine comprises L-cysteine and / or R-cysteine.