Preparation method of 2-bromo-4-chloro-3-fluorotoluene
By synthesizing 4-chlorotoluene through bromination, lithiation, borate ester reaction, ammonization and fluorination of diazotization, the problem of lack of 2-bromo-4-chloro-3-fluorotoluene synthesis method in the prior art is solved, and an efficient and simple synthesis route is achieved, which is suitable for industrial production.
Patent Information
- Application Number
- CN202510054775.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2024-12-23
- Filing Date
- 2025-01-14
- Publication Date
- 2025-04-18
AI Technical Summary
The existing technology lacks effective synthesis method of 2-bromo-4-chloro-3-fluorotoluene, which is difficult to meet its wide application needs in the fields of medicine and pesticides.
2-bromo-4-chloro-3-fluorotoluene is gradually synthesized by bromination, lithiation, borate ester reaction, ammonization, diazotization and fluorination. The catalyst and reaction conditions used in this method are simple, with high yields and are suitable for industrial production.
A simple and practical synthesis route has been developed, which solves the synthesis difficulties of multiple halogen substitutions on the benzene ring, improves yield and conversion, reduces experimental risks, and is suitable for industrial production.
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Abstract
Description
Technical Field
[0001] The invention relates to a method for preparing 2-bromo-4-chloro-3-fluorotoluene, and belongs to the technical field of preparation of pharmaceutical intermediates. Background Art
[0002] 2-Bromo-4-chloro-3-fluorotoluene is an important organic synthesis intermediate with a wide range of applications. The main uses of 2-Bromo-4-chloro-3-fluorotoluene include as a synthetic intermediate for medicines and pesticides. Because its molecular structure contains bromine, chlorine and fluorine atoms at the same time, this structure makes 2-Bromo-4-chloro-3-fluorotoluene have unique properties and uses in the fields of medicine and pesticides.
[0003] With respect to this product, after searching the literature on the prior art, no synthesis method has been reported so far.
[0004] It is necessary to conduct in-depth research on the synthetic route of 2-bromo-4-chloro-3-fluorotoluene and provide a better, simple, safe, stable and economical process route with readily available raw materials to meet the growing market demand. Summary of the invention
[0005] The technical problem to be solved by the present invention is to provide a method for preparing 2-bromo-4-chloro-3-fluorotoluene. The method provided by the present invention is to use 4-chlorotoluene as a raw material and perform bromination; then use a lithium reagent to deprotonate / boration reaction to obtain the corresponding boric acid; then convert it into an amino group under the catalysis of a copper salt; and finally perform a diazotization fluorination reaction to generate 2-bromo-4-chloro-3-fluorotoluene. In the method of the present invention, all raw materials can be easily purchased on the market, and the process of each step of the reaction is simple, the yield is high, and it is easy to industrialize production.
[0006] The objective of the present invention is achieved through the following technical solutions, and the reaction equation is expressed as follows:
[0007]
[0008] The steps include:
[0009] A. Using 4-chlorotoluene and NBS as raw materials, react in the presence of ferric bromide and thiourea catalyst to generate 2-bromo-4-chloro-toluene;
[0010] B. Deprotonate 2-bromo-4-chloro-toluene using a lithium reagent, then react with a borate ester, and generate 2-bromo-6-chloro-3-methylphenylboronic acid after hydrolysis;
[0011] C. reacting 2-bromo-6-chloro-3-methylphenylboronic acid with aqueous ammonia in the presence of cuprous oxide and DBU to generate 2-bromo-6-chloro-3-methylaniline;
[0012] D. Add 2-bromo-6-chloro-3-methylaniline, tetrafluoroboric acid and tert-butyl nitrite to an alcohol solvent and heat the reaction to generate 2-bromo-4-chloro-3-fluorotoluene.
[0013] Preferably, in the above step A, the molar ratio of the 4-chlorotoluene, NBS, ferric bromide and thiourea catalyst is 1:1-1.1:0.02-0.05:0.02-0.05.
[0014] Preferably, the above-mentioned deprotonation is carried out under low temperature conditions, and the low temperature conditions are -78°C to 0°C.
[0015] Preferably, in the above step B, the borate ester is selected from trimethyl borate, triethyl borate or triisopropyl borate.
[0016] Preferably, in the above step B, the lithiation reagent is selected from LDA or LiTMP.
[0017] Preferably, in the above step B, the molar ratio of the 2-bromo-4-chloro-toluene, the lithiation reagent and the borate ester is 1:1.1-1.5:1.2-1.5.
[0018] Preferably, in the above step C, the ammonia water is a 20-25% ammonia water solution.
[0019] Preferably, in the above step C, the molar ratio of 2-bromo-6-chloro-3-methylphenylboronic acid, cuprous oxide, aqueous ammonia and DBU is 1:0.05-0.1:1-1.5:1-1.5.
[0020] Preferably, in the above step D, the temperature is raised to 100-105°C.
[0021] Preferably, in the above step D, the molar ratio of 2-bromo-6-chloro-3-methylaniline, tetrafluoroboric acid and tert-butyl nitrite is 1:1-1.2:1-1.2.
[0022] Beneficial effects of the present invention:
[0023] A. The present invention develops a simple and practical synthesis route, which solves the difficulty of synthesizing compounds with multiple halogen substitutions on the benzene ring and provides a useful reference for the preparation of such compounds.
[0024] B. Using 4-chlorotoluene as raw material, the NBS bromination reaction was carried out under the catalytic action of ferric bromide and thiourea, and the yield was high. The thiourea catalyst greatly reduced the bromination byproducts on the methyl group of the benzene ring.
[0025] C. Aniline of the present invention undergoes diazotization and fluorination reaction under the action of fluoroboric acid and tert-butyl nitrite, with high conversion rate and reverse dropwise addition, which greatly reduces the experimental risk. BRIEF DESCRIPTION OF THE DRAWINGS
[0026] Figure 1 This is the HNMR spectrum of 2-bromo-4-chloro-3-fluorotoluene obtained in Example 5. Specific embodiments
[0027] Although the present invention has been described in detail by way of preferred embodiments, the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, a person of ordinary skill in the art may make various equivalent modifications or substitutions to the embodiments of the present invention, and these modifications or substitutions shall be within the scope of the present invention. Any person of ordinary skill in the art may easily think of changes or substitutions within the technical scope disclosed by the present invention, and these shall be within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be subject to the scope of protection described in the claims.
[0028] Example 1
[0029]
[0030] Under nitrogen protection, 12.6 g (0.1 mol) of 4-chlorotoluene, 18.7 g (0.105 mol) of NBS, 0.9 g (0.003 mol) of ferric bromide and 0.23 g (0.003 mol) of thiourea were mixed in 100 mL of dichloromethane and stirred at room temperature for 4 hours. Subsequently, 70 mL of saturated aqueous sodium thiosulfate solution was added, the layers were separated, and the mixture was extracted with dichloromethane. The organic layers were combined, concentrated, and distilled under reduced pressure to obtain 17.1 g of 2-bromo-4-chloro-toluene. The yield was 83%, and the GC was 99.2%. 1 H-NMR (400MHz, CDCl3): 7.55 (m, 1H), 7.43 (m, 1H), 7.16 (s, 1H), 2.37 (s, 3H).
[0031] Example 2
[0032]
[0033] Under nitrogen protection, 2-bromo-4-chloro-toluene 10.3g (0.05mol) was mixed in 100mL tetrahydrofuran, cooled to -20°C, 72mL 1M LDA tetrahydrofuran / hexane solution was added dropwise, the addition was completed, and the mixture was stirred for 1 hour. Then the temperature of the reaction system was reduced to -60°C to -55°C, trimethyl borate 7.3g (0.07mol) was added dropwise, the addition was completed, and the mixture was stirred for 1 hour at room temperature. After the reaction was completed, 2M hydrochloric acid was added to quench and adjust pH=2-3, ethyl acetate was extracted twice, and the mixture was washed with saturated salt water. After the solvent was evaporated, 10mL methanol was added to dissolve the mixture, and then 50mL water was added to stir and precipitate (if the precipitation speed was too slow, a few drops of hydrochloric acid could be added), and 10.1g of 2-bromo-6-chloro-3-methylphenylboronic acid was obtained by filtration and drying, with a yield of 80% and an HPLC of 99.0%. 1 HNMR (400MHz, DMSO-d6): 8.22 (s, 2H), 7.75 (m, 1H), 7.63 (m, 1H), 2.33 (s, 3H).
[0034] Example 3
[0035]
[0036] Under nitrogen protection, 10.3 g (0.05 mol) of 2-bromo-4-chloro-toluene was mixed in 90 mL of tetrahydrofuran, cooled to -10 ° C, and a solution of LiTMP (10.3 g, 0.07 mol) and tetrahydrofuran (35 mL) was added dropwise. After the addition was completed, the mixture was stirred for 2 hours. Then the temperature of the reaction system was lowered to -60 ° C to -55 ° C, and 7.3 g (0.07 mol) of trimethyl borate was added dropwise. After the addition was completed, the mixture was stirred for 2 hours. The mixture was naturally heated to room temperature and stirred for 2 hours. After the reaction was completed, 2 M hydrochloric acid was added to quench and adjust the pH to 2-3. The mixture was extracted with ethyl acetate twice, washed with saturated brine, evaporated the solvent, added 10 mL of methanol to dissolve, and then added 50 mL of water to stir and precipitate. Filtered and dried to obtain 9.0 g of 2-bromo-6-chloro-3-methylphenylboronic acid, with a yield of 72%, and HPLC 99.0%.
[0037] Example 4
[0038]
[0039] Under nitrogen protection, 12.5 g (0.05 mol) of 2-bromo-6-chloro-3-methylphenylboronic acid, 0.57 g (0.004 mol) of cuprous oxide, 9.8 g of ammonia water and 8.4 g (0.055 mol) of DBU were mixed in 100 mL of THF and stirred at room temperature for 6 hours. 100 mL of dichloromethane was added, and the layers were separated. The organic layer was washed twice with 50 mL of deionized water. The organic layer was concentrated and the crude product was purified by column chromatography with eluent ethyl acetate / n-hexane (v / v=1 / 8) to give 7.7 g of 2-bromo-6-chloro-3-methylaniline in a yield of 70% and an HPLC yield of 98.6%. 1 HNMR(400MHz, CDCl3):7.33(m,1H),7.23(m,1H),4.55(s,2H),2.31(s,3H).
[0040] Example 5
[0041]
[0042] Under nitrogen protection, 11 g (0.05 mol) of 2-bromo-6-chloro-3-methylaniline was mixed in 70 mL of ethanol, 12.1 g of 40% tetrafluoroboric acid was added, the reaction solution was cooled to 0°C, 6.3 g of 90% tert-butyl nitrite (t-BuONO) was slowly added, and then the reaction solution was slowly heated to room temperature and reacted for 1 hour. After the reaction was completed, 70 mL of DMSO was added until the reaction solution was completely dissolved.
[0043] Under nitrogen protection, add 200 mL of toluene to the reaction bottle and heat to 100-105°C. Slowly add the above reaction solution dropwise to the toluene reaction bottle, and gas is continuously released. After the dropwise addition is completed, continue the reaction for 1 hour, cool to room temperature, add 100 mL of saturated sodium bicarbonate, separate the layers, extract the aqueous layer once with 100 mL of toluene, combine the organic layers, concentrate, and purify the crude product by column chromatography with eluent ethyl acetate / n-hexane (v / v=1 / 5-20) to obtain 8.7 g of 2-bromo-4-chloro-3-fluorotoluene with a yield of 78% and an HPLC yield of 99.1%. 1 HNMR (400MHz, CDCl3): 7.23 (m, 1H), 6.98 (m, 1H), 2.41 (s, 3H).
[0044] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.
Claims
1. A method for preparing 2-bromo-4-chloro-3-fluorotoluene, characterized in that: The steps include: A. Using 4-chlorotoluene and NBS as raw materials, react in the presence of ferric bromide and thiourea catalyst to generate 2-bromo-4-chloro-toluene; B. Deprotonate 2-bromo-4-chloro-toluene using a lithium reagent, then react with a borate ester, and generate 2-bromo-6-chloro-3-methylphenylboronic acid after hydrolysis; C. reacting 2-bromo-6-chloro-3-methylphenylboronic acid with aqueous ammonia in the presence of cuprous oxide and DBU to generate 2-bromo-6-chloro-3-methylaniline; D. Add 2-bromo-6-chloro-3-methylaniline, tetrafluoroboric acid and tert-butyl nitrite to an alcohol solvent and heat the reaction to generate 2-bromo-4-chloro-3-fluorotoluene.
2. The method for preparing 2-bromo-4-chloro-3-fluorotoluene according to claim 1, characterized in that: In step A, the molar ratio of 4-chlorotoluene, NBS, ferric bromide and thiourea catalyst is 1:1-1.1:0.02-0.05:0.02-0.
05.
3. The method for preparing 2-bromo-4-chloro-3-fluorotoluene according to claim 1, characterized in that: In step B, the deprotonation is carried out under low temperature conditions, which are -78°C to 0°C.
4. The method for preparing 2-bromo-4-chloro-3-fluorotoluene according to claim 1, characterized in that: In step B, the borate ester is selected from trimethyl borate, triethyl borate or triisopropyl borate.
5. The method for preparing 2-bromo-4-chloro-3-fluorotoluene according to claim 1, characterized in that: In step B, the lithiation reagent is selected from LDA or LiTMP.
6. The method for preparing 2-bromo-4-chloro-3-fluorotoluene according to claim 1, characterized in that: In step B, the molar ratio of 2-bromo-4-chloro-toluene, the lithiation reagent and the borate ester is 1:1.1-1.5:1.2-1.
5.
7. The method for preparing 2-bromo-4-chloro-3-fluorotoluene according to claim 1, characterized in that: In step C, the ammonia water is a 20-25% ammonia water solution.
8. The method for preparing 2-bromo-4-chloro-3-fluorotoluene according to claim 1, characterized in that: In step C, the molar ratio of 2-bromo-6-chloro-3-methylphenylboronic acid, cuprous oxide, aqueous ammonia and DBU is 1:0.05-0.1:1-1.5:1-1.
5.
9. The method for preparing 2-bromo-4-chloro-3-fluorotoluene according to claim 1, characterized in that: In step D, the temperature is raised to 100-105°C.
10. The method for preparing 2-bromo-4-chloro-3-fluorotoluene according to claim 1, characterized in that: In step D, the molar ratio of 2-bromo-6-chloro-3-methylaniline, tetrafluoroboric acid and tert-butyl nitrite is 1:1-1.2:1-1.2.