Synthesis method of 3-bromo-6-chloro-2-fluorobenzoic acid

Abstract

The invention discloses a synthesis method of 3-bromo-6-chloro-2-fluorobenzoic acid, and is characterized in that the synthesis method of 3-bromo-6-chloro-2-fluorobenzoic acid comprises the following steps: S1001, dissolving 2-chloro-6-fluorobromobenzene in an organic solvent I, cooling to-80 DEG C to-50 DEG C, then adding a lithium diisopropylamide solution, stirring for 20-40 minutes, then adding dry ice, stirring for 20-40 minutes, cooling to-80 DEG C to-50 DEG C, cooling to-80 DEG C to-50 DEG C, then adding 2-chloro-6-fluorobromobenzene, and then adding an organic solvent II; and then naturally heating to room temperature, and stirring to react for 10-30 hours. And S1002, after the reaction is completed, carrying out post-treatment on the reaction liquid to obtain the target compound 3-bromine-6-chloro-2-fluorobenzoic acid.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for synthesizing 3-bromo-6-chloro-2-fluorobenzoic acid. Background Technology

[0002] Halogenated benzoic acids are an important class of organic compounds with wide applications in life sciences, medicine, and chemistry. 3-Bromo-6-chloro-2-fluorobenzoic acid is an important halogenated benzoic acid compound and a crucial molecular building block. As a key intermediate, it was used in patent CN109232533A for the synthesis of a nitrogen-containing heterocyclic derivative, which, as an SMO antagonist, can be used to treat diseases related to the Hedgehog signaling pathway, such as cancer; in patent WO2004 / 048314 for the synthesis of a cyclooxygenase 2 (COX-2) inhibitor, which has some effect on the treatment of COX-2-dependent diseases; and in patent WO2015 / 170218 for the synthesis of a TrkA antagonist.

[0003] In existing technologies, the conventional synthetic route for 3-bromo-6-chloro-2-fluorobenzoic acid uses 1-bromo-4-chloro-2-fluorobenzene as a starting material and proceeds through a one-step reaction. However, this method generates byproducts and results in unsatisfactory yields, generally below 85%, and rarely exceeding 90%. Therefore, developing a novel synthetic method for 3-bromo-6-chloro-2-fluorobenzoic acid is of great significance. Summary of the Invention

[0004] To solve the above technical problems, this application provides a method for synthesizing 3-bromo-6-chloro-2-fluorobenzoic acid, the method comprising the following steps: S1001, dissolve 2-chloro-6-fluorobromobenzene in organic solvent I, cool to -80℃~-50℃, then add diisopropylaminolithium solution, stir for 20~40 minutes, add dry ice, then let it rise naturally to room temperature, and stir for 10~30 hours. After the reaction was completed (S1002), the reaction solution was post-treated to obtain the target compound 3-bromo-6-chloro-2-fluorobenzoic acid.

[0005] Preferably, the organic solvent I is selected from one or more of tetrahydrofuran, diethyl ether, and methyl tert-butyl ether.

[0006] Preferably, the diisopropylaminolithium solution is selected from at least one of the following: diisopropylaminolithium dissolved in n-hexane solution, diisopropylaminolithium dissolved in n-ethane solution, and diisopropylaminolithium dissolved in tetrahydrofuran solution.

[0007] Preferably, the molar ratio of 2-chloro-6-fluorobromobenzene to lithium diisopropylaminodimethylbenzene is 1:1.0 to 1.5.

[0008] Preferably, the mass-to-volume ratio (g / mL) of the 2-chloro-6-fluorobromobenzene to organic solvent I is 1:5 to 40.

[0009] Preferably, the mass ratio of 2-chloro-6-fluorobromobenzene to dry ice is 1:4 to 6.

[0010] Preferably, the post-processing procedure is as follows: after the reaction is complete, the reaction solution is quenched with a saturated ammonium chloride aqueous solution, extracted with organic solvent II, the organic phases are combined, the organic phases are concentrated to obtain a crude product, and the crude product is purified to obtain the target compound 3-bromo-6-chloro-2-fluorobenzoic acid.

[0011] Preferably, the organic solvent II is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, or dichloroethane.

[0012] Preferably, the purification method is selected from one or more of pulping, column chromatography, recrystallization, or distillation.

[0013] According to another aspect of this application, this application provides 3-bromo-6-chloro-2-fluorobenzoic acid, which is prepared by any of the above-described methods for synthesizing 3-bromo-6-chloro-2-fluorobenzoic acid.

[0014] The beneficial technical effects of this invention are as follows: This invention proposes a method for synthesizing 3-bromo-6-chloro-2-fluorobenzoic acid. Using 2-chloro-6-fluorobromobenzene as a raw material, the target compound 3-bromo-6-chloro-2-fluorobenzoic acid is obtained by rearrangement and carboxylation reaction under the action of diisopropylaminolithium and carbon dioxide.

[0015] The present invention creatively uses 2-chloro-6-fluorobromobenzene as a starting material instead of 1-bromo-4-chloro-2-fluorobenzene, resulting in no byproducts generated in the reaction, simplified post-processing and purification, and a significantly improved yield of the target compound, achieving an ideal yield. This provides a potential route for the scale-up of the 3-bromo-6-chloro-2-fluorobenzoic acid process. Attached Figure Description

[0016] Figure 1 This is a schematic diagram of the process for preparing 3-bromo-6-chloro-2-fluorobenzoic acid.

[0017] Figure 2 The image shows the 1H NMR spectrum of 3-bromo-6-chloro-2-fluorobenzoic acid prepared in Example 1 of this invention. Detailed Implementation

[0018] The preferred embodiments described below are merely examples, and other obvious variations will be apparent to those skilled in the art. The basic principles of the invention defined in the following description can be applied to other embodiments, modifications, improvements, equivalents, and other technical solutions that do not depart from the spirit and scope of the invention.

[0019] A preferred embodiment of the present invention provides a method for synthesizing 3-bromo-6-chloro-2-fluorobenzoic acid, the method comprising the following steps: S1001, dissolve 2-chloro-6-fluorobromobenzene in organic solvent I, cool to -80℃~-50℃, then add diisopropylaminolithium solution, stir for 20~40 minutes, add dry ice, then let it rise naturally to room temperature, and stir for 10~30 hours. After the reaction was completed (S1002), the reaction solution was post-treated to obtain the target compound 3-bromo-6-chloro-2-fluorobenzoic acid.

[0020] In one embodiment, in step S1001, the organic solvent I is selected from one or more of tetrahydrofuran, diethyl ether, and methyl tert-butyl ether.

[0021] In one embodiment, in step S1001, the diisopropylaminolithium solution is selected from at least one of diisopropylaminolithium dissolved in n-hexane, diisopropylaminolithium dissolved in n-ethane, and diisopropylaminolithium dissolved in tetrahydrofuran.

[0022] Preferably, in step S1001, the molar ratio of 2-chloro-6-fluorobromobenzene to diisopropylaminolithium is 1:1.0 to 1.5.

[0023] In one embodiment, in step S1001, the mass-to-volume ratio of 2-chloro-6-fluorobromobenzene to organic solvent I is 1:5 to 40 (g / mL).

[0024] Preferably, in step S1001, the mass ratio of 2-chloro-6-fluorobromobenzene to dry ice is 1:4 to 6.

[0025] More preferably, the post-treatment process is as follows: after the reaction is complete, the reaction solution is quenched with a saturated ammonium chloride aqueous solution, extracted with organic solvent II, the organic phases are combined, the organic phases are concentrated to obtain a crude product, and the crude product is purified to obtain the target compound 3-bromo-6-chloro-2-fluorobenzoic acid.

[0026] Preferably, the organic solvent II is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, or dichloroethane.

[0027] Preferably, the purification method is selected from one or more of pulping, column chromatography, recrystallization, or distillation.

[0028] Example 1

[0029] A method for synthesizing 3-bromo-6-chloro-2-fluorobenzoic acid, comprising the following steps: (1) Compound 1, namely 2-chloro-6-fluorobromobenzene (200.00 g, 954.92 mmol, 1.00 eq), was dissolved in tetrahydrofuran (2.0 L). After cooling to -60 °C, a solution of diisopropylaminolithium (572.95 mL, 1.15 mol, 1.20 eq, 2.00 M in THF) was added. After stirring for 30 minutes, dry ice (1000 g) was added, and the mixture was allowed to rise naturally to room temperature. The mixture was stirred and reacted for 12 hours.

[0030] (2) After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride aqueous solution and extracted twice with dichloromethane (1.5 L × 2). The organic phases were combined and concentrated to obtain crude product. The crude product was purified by slurrying with a mixed organic solvent of petroleum ether and ethyl acetate in a volume ratio of 5:1 to obtain the target compound 3-bromo-6-chloro-2-fluorobenzoic acid (weight 238.10 g, purity 98%, yield 96%).

[0031] The 1H NMR spectrum of the obtained compound 2 (3-bromo-6-chloro-2-fluorobenzoic acid) is as follows: Figure 1 As shown, the characterization data is as follows: 1 H NMR (400 MHz, DMSO) δ 14.30 (s, 1H), 7.79 (dd, J = 8.4, 7.9 Hz, 1H), 7.36 (dd, J = 8.7, 1.1 Hz, 1H). Example 2-3 The synthesis methods of Examples 2-3 are basically the same as those of Example 1, except that the molar amounts of diisopropylaminolithium in step (1) of Examples 2-3 are 954.92 mmol and 1.43 mol respectively. The rest remains unchanged. The yields of 3-bromo-6-chloro-2-fluorobenzoic acid in Examples 2-3 are shown in Table 1.

[0032] Examples 4-6 The synthesis methods of Examples 4-6 are basically the same as those of Example 1. The only difference is that the mass of dry ice in step (1) of Examples 4-6 is 400g, 800g and 1400g respectively. The rest remains unchanged. The yield of 3-bromo-6-chloro-2-fluorobenzoic acid in Examples 4-6 is shown in Table 1.

[0033] Examples 7-8 The synthesis methods of Examples 7-8 are basically the same as those of Example 1, except that the organic solvent I in step (1) of Examples 7-8 is 2-methyltetrahydrofuran and diethyl ether, respectively. The rest of the contents remain unchanged. The yield of 3-bromo-6-chloro-2-fluorobenzoic acid in Examples 7-8 is shown in Table 1.

[0034] Examples 9-10 The synthesis methods of Examples 9-10 are basically the same as those of Example 1. The only difference is that the stirring reaction time in step (1) of Examples 9-10 is 10h and 30h respectively. The rest remains unchanged. The yield of 3-bromo-6-chloro-2-fluorobenzoic acid in Examples 9-10 is shown in Table 1.

[0035] Table 1 Synthesis conditions and yield results of 3-bromo-6-chloro-2-fluorobenzoic acid for each example

[0036] As can be seen from the results in Table 1, The results of Examples 1-3 show that when the molar ratio of compound 1 to lithium diisopropylamino is 1.0:1.0~1.5, the yield of the target compound 3-bromo-6-chloro-2-fluorobenzoic acid is relatively high. Among them, the product yields are basically the same when the molar ratio of compound 1 to lithium diisopropylamino is 1.0:1.2 and 1.0:1.5.

[0037] The results from Examples 1 and 4-6 show that when the mass ratio of compound 1 to dry ice is 1.0:2.0 to 7.0, the yield of the target compound 3-bromo-6-chloro-2-fluorobenzoic acid is relatively high. Among them, the product yields are basically the same when the mass ratio of compound 1 to dry ice is 1.0:5.0 and 1.0:7.0.

[0038] In Examples 1 and 7-8, tetrahydrofuran, 2-methyltetrahydrofuran, and diethyl ether were used as solvents for the reaction, respectively. The reaction proceeded smoothly, and the yield of the target compound 3-bromo-6-chloro-2-fluorobenzoic acid was high. Among them, the reaction with tetrahydrofuran as solvent had the highest yield.

[0039] The results from Examples 1 and 9-10 show that the reaction effect is basically optimal when the reaction time reaches 12 h.

[0040] The synthesis method of the present invention yields 90-96% of 3-bromo-6-chloro-2-fluorobenzoic acid, which is significantly higher than the synthesis method disclosed in prior art patent CN109232533A.

[0041] Those skilled in the art should understand that the embodiments of the present invention described above are merely examples and do not limit the invention. The objectives of the present invention have been fully and effectively achieved. The functions and structural principles of the present invention have been shown and explained in the embodiments, and any modifications or variations of the implementation of the present invention may be made without departing from the stated principles.

Claims

1. A method for synthesizing 3-bromo-6-chloro-2-fluorobenzoic acid, characterized in that, The method for synthesizing the 3-bromo-6-chloro-2-fluorobenzoic acid includes the following steps: S1001, dissolve 2-chloro-6-fluorobromobenzene in organic solvent I, cool to -80℃~-50℃, then add diisopropylaminolithium solution, stir for 20~40 minutes, add dry ice, then let it rise naturally to room temperature, and stir for 10~30 hours. After the reaction was completed (S1002), the reaction solution was post-treated to obtain the target compound 3-bromo-6-chloro-2-fluorobenzoic acid.

2. The method for synthesizing 3-bromo-6-chloro-2-fluorobenzoic acid according to claim 1, characterized in that, The organic solvent I is selected from one or more of tetrahydrofuran, diethyl ether, and methyl tert-butyl ether.

3. The method for synthesizing 3-bromo-6-chloro-2-fluorobenzoic acid according to claim 1, characterized in that, The diisopropylaminolithium solution is configured to be at least one selected from diisopropylaminolithium dissolved in n-hexane, diisopropylaminolithium dissolved in n-hexane, and diisopropylaminolithium dissolved in tetrahydrofuran.

4. The method for synthesizing 3-bromo-6-chloro-2-fluorobenzoic acid according to claim 1, characterized in that, The molar ratio of 2-chloro-6-fluorobromobenzene to lithium diisopropylaminodimethylbenzene is 1:1.0 to 1.

5.

5. The method for synthesizing 3-bromo-6-chloro-2-fluorobenzoic acid according to claim 1, characterized in that, The mass-to-volume ratio (g / mL) of the 2-chloro-6-fluorobromobenzene to organic solvent I is 1:5 to 40.

6. The method for synthesizing 3-bromo-6-chloro-2-fluorobenzoic acid according to claim 1, characterized in that, The mass ratio of 2-chloro-6-fluorobromobenzene to dry ice is 1:4 to 6.

7. The method for synthesizing 3-bromo-6-chloro-2-fluorobenzoic acid according to claim 1, characterized in that, The specific post-processing procedure is as follows: after the reaction is complete, the reaction solution is quenched with saturated ammonium chloride aqueous solution, extracted with organic solvent II, the organic phases are combined, the organic phases are concentrated to obtain crude product, and the crude product is purified to obtain the target compound 3-bromo-6-chloro-2-fluorobenzoic acid.

8. The method for synthesizing 3-bromo-6-chloro-2-fluorobenzoic acid according to claim 7, characterized in that, The organic solvent II is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, or dichloroethane.

9. The method for synthesizing 3-bromo-6-chloro-2-fluorobenzoic acid according to claim 7, characterized in that, The purification method is selected from one or more of pulping, column chromatography, recrystallization, or distillation.

10. A 3-bromo-6-chloro-2-fluorobenzoic acid, characterized in that, It is prepared by the synthetic method of any one of claims 1-9 for 3-bromo-6-chloro-2-fluorobenzoic acid.

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