A method for synthesizing polyhalogen-substituted fluorine-containing 2-bromobenzoic acid compounds

Abstract

The invention discloses a method for synthesizing a polyhalogen-substituted fluorine-containing 2-bromobenzoic acid compound, using fluorine-containing 2-bromopolyhalogenated benzene as a raw material, using conventional lithium reagents, using multiple ligands and strictly controlling the system temperature, to achieve a target compound by positioning the carbonylation at the ortho-position of bromine. The synthesis method of the invention avoids the carbonylation side reaction of the fluorine-containing aromatic substrate at the ortho-position of the fluorine atom under the conditions of conventional lithium reagents, and on the other hand breaks the inherent thinking of the existing synthesis route of such compounds, is a stable route with high reaction selectivity, ideal yield and simple product post-processing, and provides a new idea for synthesizing polyhalogen-substituted fluorine-containing 2-bromobenzoic acid compounds.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediates, and specifically relates to a method for synthesizing a polyhalogen-substituted fluorine-containing 2-bromobenzoic acid compound. Background Art

[0002] Polyhalogen substituted fluorinated 2-bromobenzoic acid ( Figure 1 ) is an important benzoic acid derivative. Because it contains multiple halogen atoms and has many active sites, it can be assembled in various modes to construct a large number of different target compounds. It is a molecular building block with great application potential. For example, 2-bromo-6-chloro-3-fluorobenzoic acid was reported as a key intermediate to synthesize a new type of diaryl ether herbicide. The resulting target 3-chloro-6-fuoro-2-(3,5-dichlorophenoxy)benzoic acid showed excellent control over weeds such as sunflower, ivy, and morning glory, and had ideal control over Setaria viridis (giant foxtail) (J. Agric. Food Chem. 2023, 71, 18171-18187). In addition, this new type of diaryl ether compound is expected to show more vitality in other fields.

[0003] Given the high application potential of polyhalogen-substituted fluorinated 2-bromobenzoic acid compounds and their use in novel diaryl ether herbicides, it is necessary to study their synthesis methods. In the prior art, in the preparation methods of polyhalogen-substituted fluorinated 2-bromobenzoic acid compounds, in order to avoid the ortho-position effect of the F fluorine atom, most of them use polyhalogen-substituted 2-aminobenzoic acid to perform diazotization of the 2-amino group to prepare 2-bromobenzoic acid compounds. Taking the preparation of 2-bromo-4-fluorobenzoic acid as an example, 2-amino-4-fluorobenzoic acid is used as a raw material, and the 2-amino group is converted into a bromine atom ( Figure 2 ), to obtain the target compound (DE4200512A1). Alternatively, 1-bromo-2-iodophenyl substituent is used to prepare 2-bromobenzoic acid compounds by metal reagent extraction of iodine and insertion of carbonyl, taking the preparation of 2-bromo-3-fluorobenzoic acid as an example ( Figure 3 ), using 2-bromo-1-fluoro-3-iodobenzene as raw material, through the positioning effect of iodine atom and n-butyl lithium reagent, iodine is extracted and carbonyl is inserted to obtain the target 2-bromo-3-fluorobenzoic acid (SYNTHESIS 2005, No.4, pp 0617-0621).

[0004] The above-mentioned prior art often needs to find the corresponding aminobenzoic acid raw materials or iodophenyl compound raw materials when synthesizing polyhalogen-substituted fluorine-containing 2-bromobenzoic acid compounds. These raw materials are often difficult to obtain, resulting in certain limitations in the prior art, which to a certain extent restricts the development and application of such compounds. Summary of the invention

[0005] The object of the present invention is to provide a method for synthesizing a polyhalogen-substituted fluorine-containing 2-bromobenzoic acid compound, which has the advantages of simple operation, stable process, easy availability of raw materials, and avoidance of the influence of the positioning of the substrate fluorine atoms.

[0006] To achieve the above object, the present invention adopts the following technical solution:

[0007] A method for synthesizing a polyhalogen-substituted fluorine-containing 2-bromobenzoic acid compound, the synthesis route of which is shown in Formula 1 below:

[0008]

[0009] The synthesis method comprises the following steps:

[0010] (1) Under nitrogen protection, solvent 1 is cooled to T1, diisopropylamine is added and stirred for 0.5 to 1 hour; then 2,2,6,6-tetramethylpiperidine is added to the reaction system while maintaining the temperature of T1, and stirred for 0.5 to 1 hour; lithium reagent is slowly added dropwise, and stirred for 1 to 2 hours; then compound 1 is slowly added to the reaction system, and stirred for 0.5 to 3 hours; dry ice is added to the reaction system, and then the temperature is naturally raised to T2, and stirred for 1 to 4 hours, and the reaction is complete;

[0011] (2) adding alkaline solution to adjust the pH value of the reaction system to 10-12, back-extracting with solvent 2, discarding the organic phase, retaining the aqueous phase, and then adjusting the pH value of the aqueous phase to 2-3 with a strong acid solution, extracting with solvent 2 again, and distilling the obtained organic phase under reduced pressure to remove the solvent to obtain the product.

[0012] Furthermore, in Formula 1, X is selected from one of H, Br, and Cl.

[0013] Furthermore, in Formula 1, F is one or more of 3-position, 4-position, and 5-position substitutions, and n represents the number of Fs, which is selected from 1, 2, or 3.

[0014] Furthermore, in step (1), the solvent 1 is selected from one or more of tetrahydrofuran, diethyl ether, and N-methylpyrrolidone, and the mass volume ratio of the compound 1 to the solvent 1 is 1 g: 3 to 20 mL.

[0015] Furthermore, in step (1), T1 is -45 to -20°C, and more preferably -30°C.

[0016] Furthermore, in step (1), the molar ratio of compound 1, diisopropylamine, 2,2,6,6-tetramethylpiperidine and lithium reagent is 1:1-1.5:0.5-1.0:1.0-1.5, and is further preferably 1:1.2:0.6:1.05.

[0017] Furthermore, in step (1), the mass ratio of the compound 1 to dry ice is 1:1-2, and more preferably 1:2.

[0018] Furthermore, in step (1), the lithium reagent is n-butyllithium.

[0019] Furthermore, in step (1), T2 is 20 to 35°C.

[0020] Furthermore, in step (1), diisopropylamine was added and stirred for 0.5 h, 2,2,6,6-tetramethylpiperidine was added and stirred for 0.5 h, lithium reagent was added and stirred for 1 h, compound 1 was added and stirred for 1 h, and the temperature was raised to T2 and then the reaction was kept warm for 2 h.

[0021] Furthermore, in step (2), the solvent 2 is selected from one or more of ethyl acetate, dichloromethane, and dichloroethane, and the mass volume ratio of the compound 1 to the solvent 2 is 1 g: 5 to 50 mL.

[0022] Furthermore, in step (2), the alkali solution is an aqueous solution selected from sodium hydroxide, sodium carbonate, and sodium bicarbonate with a concentration of 0.5 to 2.0 mol, and is more preferably a 1.0 mol sodium hydroxide aqueous solution.

[0023] Furthermore, in step (2), the pH of the reaction system is 11 after adding the alkali solution.

[0024] Furthermore, in step (2), the strong acid solution is an aqueous solution of hydrochloric acid or sulfuric acid with a concentration of 1.0 to 2.0 mol, and more preferably a 1 mol hydrochloric acid aqueous solution.

[0025] Furthermore, in step (2), the pH of the reaction system is 2 after the acid solution is added.

[0026] Compared with the prior art, the beneficial effects of the present invention are as follows: the present invention adopts more easily available fluorine-containing 2-bromopolyhalogenated benzene as a raw material, uses conventional lithium reagents, uses multiple ligands and controls the system temperature to construct an ideal system, thereby performing carbonyl insertion at the ortho position of bromine to obtain a target compound. On the one hand, the carbonyl insertion side reaction of the fluorine-containing aromatic substrate at the ortho position of the fluorine atom under the conditions of conventional lithium reagents is avoided, and on the other hand, the inherent thinking that the polyhalogen-substituted fluorine-containing 2-bromobenzoic acid compounds are synthesized through group conversion through amino groups or through positioning groups such as iodine atoms for positioning carbonyl insertion is broken. The present invention is a stable route with high reaction selectivity, ideal yield and simple product post-processing, which provides a new idea for the synthesis of polyhalogen-substituted fluorine-containing 2-bromobenzoic acid compounds and further lays a foundation for the application of such compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 is the general structure of the target compound.

[0028] Figure 2 It is a synthetic route of 2-bromo-4-fluorobenzoic acid in the prior art.

[0029] Figure 3 It is a synthetic route of 2-bromo-3-fluorobenzoic acid in the prior art.

[0030] Figure 4 This is the synthetic route of the polyhalogen-substituted fluorine-containing 2-bromobenzoic acid compounds in the examples.

[0031] Figure 5 This is the H NMR spectrum of 2-bromo-6-chloro-3-fluorobenzoic acid prepared in Example 1.

[0032] Figure 6 This is the H NMR spectrum of 2-bromo-6-chloro-4-fluorobenzoic acid obtained in Example 8. DETAILED DESCRIPTION

[0033] In order to make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be clearly and completely described below in combination with the embodiments and drawings. Obviously, the described embodiments are part of the embodiments of the present invention, not all of them, and all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0034] The preparation of polyhalogen-substituted fluorine-containing 2-bromobenzoic acid compounds in the prior art is limited by the reaction raw materials. At the same time, due to the characteristics of the fluorine atoms on the substrate, side reactions caused by the positioning effect of the fluorine atoms need to be avoided during the reaction. The present invention aims to provide a synthetic route for polyhalogen-substituted fluorine-containing 2-bromobenzoic acid compounds with high selectivity, ideal yield and simple product post-treatment.

[0035] Example 1

[0036] This example synthesizes 2-bromo-6-chloro-3-fluorobenzoic acid, and the synthesis route is as follows:

[0037]

[0038] The specific steps include:

[0039] (1) Under nitrogen protection, tetrahydrofuran (40 mL) was cooled to -30 ° C, diisopropylamine (1.2 eq, 11.6 g) was added, and the mixture was stirred for 0.5 h. Then, 2,2,6,6-tetramethylpiperidine (0.6 eq, 8.09 g) was added to the reaction system, and the mixture was stirred for 0.5 h. n-Butyl lithium (1.05 eq, 40 mL) was slowly added dropwise, and the mixture was stirred for 1 h. Then, compound 1a (1.0 eq, 20.0 g) was slowly added to the reaction system, and the mixture was stirred at -30 ° C for 1 h. Dry ice (40 g) was added to the reaction system, and then the temperature was naturally raised to 25 ° C, and the mixture was stirred for 2 h.

[0040] (2) 1 mol of sodium hydroxide aqueous solution was added to the reaction system, the pH of the system was adjusted to 11, impurities were extracted with ethyl acetate (400 mL), the aqueous phases were combined, and the organic phases were discarded. The obtained aqueous phase was adjusted to pH 2 with 1 mol of hydrochloric acid aqueous solution, extracted with ethyl acetate (400 mL), the organic phases were combined, and the solvent was removed by reduced pressure distillation to obtain 21.1 g of light yellow solid with a purity of 98.5% and a yield of 85.87%.

[0041] like Figure 5 As shown, the NMR data of compound 1a 2-bromo-6-chloro-3-fluorobenzoic acid are as follows:

[0042] 1 H NMR (400MHz, cdcl3) δ7.55 (dd, J=9.0, 5.2Hz, 1H), 7.12 (t, J=8.6Hz, 1H).

[0043] The following Examples 2 to 7 and Comparative Examples 1 to 3 further analyze the effect of changes in reaction conditions in each reaction step on the product yield, as shown in Table 1.

[0044] Table 1

[0045] Serial number Reaction condition variables Yield purity Example 2 1.0eq 2,2,6,6-Tetramethylpiperidine 73.21％ 94.30％ Example 3 0.5eq 2,2,6,6-Tetramethylpiperidine 79.31％ 95.51％ Example 4 T1＝-45℃ 69.37％ 93.29％ Example 5 T1＝-20℃ 65.85％ 94.59％ Example 6 Heat to T2 and react for 4h 76.54％ 93.22％ Example 7 1.5eq diisopropylamine 70.43％ 92.01％ Comparative Example 1 T1＝-78℃ 22.12％ / Comparative Example 2 0eq 2,2,6,6-Tetramethylpiperidine 12.25％ / Comparative Example 3 0eq diisopropylamine 18.35％ /

[0046] In Example 2, Example 3 and Comparative Example 2, compared with Example 1, the amount of 2,2,6,6-tetramethylpiperidine in the reaction was changed. Relative to Example 1, the lower the amount of 2,2,6,6-tetramethylpiperidine, the lower the yield. When its amount was increased, the reaction yield also showed a decreasing trend. When its amount was reduced to 0 eq, only a very small amount of the target compound was obtained.

[0047] In Example 4 and Example 5 and Comparative Example 1, compared with Example 1, changing the temperature of T1 in the reaction and lowering the reaction temperature will cause the reaction to tend towards a side reaction. When T1 is reduced to -78°C, the reaction yield is significantly reduced; increasing the reaction temperature also promotes the occurrence of side reactions, and the reaction yield is reduced.

[0048] In Example 6, compared with Example 1, the reaction time after the temperature of the reaction system is raised to T2 is prolonged. The prolonged reaction time provides an opportunity for side reactions to occur, thereby reducing the reaction yield.

[0049] In Example 7 and Comparative Example 3, compared with Example 1, the amount of diisopropylamine in the reaction system was changed, the amount of diisopropylamine increased, the by-products increased, and the reaction yield decreased. When the amount of diisopropylamine was 0 eq, the reaction yield decreased significantly, indicating that the role of diisopropylamine in the reaction is indispensable.

[0050] Example 8

[0051] This example synthesizes 2-bromo-6-chloro-4-fluorobenzoic acid, and the synthesis route is as follows:

[0052]

[0053] The specific steps include:

[0054] (1) Under nitrogen protection, tetrahydrofuran (60 mL) was cooled to -30 °C, diisopropylamine (1.2 eq, 17.4 g) was added, and the mixture was stirred for 0.5 h. Then, 2,2,6,6-tetramethylpiperidine (0.6 eq, 12.2 g) was added to the reaction system, and the mixture was stirred for 0.5 h. Then, n-butyl lithium (1.05 eq, 60 mL) was slowly added dropwise, and the mixture was stirred for 1 h. Then, compound 1b (1.0 eq, 30.0 g) was slowly added to the reaction system, and the mixture was stirred at -30 °C for 1 h. Then, dry ice (60 g) was added to the reaction system, and the temperature was naturally raised to 25 °C, and the mixture was stirred for 2 h.

[0055] (2) 1 mol of sodium hydroxide aqueous solution was added to the reaction system, the pH of the system was adjusted to 11, impurities were extracted with ethyl acetate (600 mL), the aqueous phases were combined, and the organic phases were discarded. The obtained aqueous phase was adjusted to pH 2 with 1 mol of hydrochloric acid aqueous solution, extracted with ethyl acetate (600 mL), the organic phases were combined, and the solvent was removed by reduced pressure distillation to obtain 32.24 g of light yellow solid with a purity of 97.12% and a yield of 88.87%.

[0056] like Figure 6 As shown, the NMR data of compound 1b 2-bromo-6-chloro-4-fluorobenzoic acid are as follows:

[0057] 1 H NMR (400MHz, DMSO) δ14.15(s,1H),7.75(dd,J=8.3,2.4Hz,1H),7.67(dd,J=8.7,2.3Hz,1H).

[0058] In summary, the present invention proposes a method for synthesizing a polyhalogen-substituted fluorine-containing 2-bromobenzoic acid compound, which uses fluorine-containing 2-bromopolyhalogenated benzene as a raw material, uses conventional lithium reagents, uses multiple ligands and controls the system temperature, and performs carbonylation at the ortho position of bromine to obtain the target compound, breaking the inherent strategy used in the synthesis of this type of compound. It is a stable route with high reaction selectivity, ideal yield and simple product post-processing.

[0059] The above is only a preferred embodiment of the present invention, but the present invention should not be limited to the contents disclosed in this embodiment. Any equivalent or modification completed without departing from the spirit disclosed in the present invention shall fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing a polyhalogen-substituted fluorine-containing 2-bromobenzoic acid compound, characterized in that: The synthetic route is shown in Formula 1 below: The synthesis method comprises the following steps: (1) Under nitrogen protection, solvent 1 is cooled to T1, diisopropylamine is added and stirred for 0.5 to 1 hour; then 2,2,6,6-tetramethylpiperidine is added to the reaction system while maintaining the temperature of T1, and stirred for 0.5 to 1 hour; lithium reagent is slowly added dropwise, and stirred for 1 to 2 hours; then compound 1 is slowly added to the reaction system, and stirred for 0.5 to 3 hours; dry ice is added to the reaction system, and then the temperature is naturally raised to T2, and stirred for 1 to 4 hours, and the reaction is complete; (2) adding alkaline solution to adjust the pH value of the reaction system to 10-12, back-extracting with solvent 2, discarding the organic phase, retaining the aqueous phase, and then adjusting the pH value of the aqueous phase to 2-3 with a strong acid solution, extracting with solvent 2 again, and distilling the obtained organic phase under reduced pressure to remove the solvent to obtain the product.

2. The method for synthesizing the polyhalogen-substituted fluorine-containing 2-bromobenzoic acid compound according to claim 1, characterized in that: In Formula 1, X is selected from one of H, Br and Cl.

3. The method for synthesizing the polyhalogen-substituted fluorine-containing 2-bromobenzoic acid compound according to claim 1, characterized in that: In Formula 1, F is one or more of 3-position, 4-position, and 5-position substitutions, and n represents the number of Fs, which is selected from 1, 2, or 3.

4. The method for synthesizing the polyhalogen-substituted fluorine-containing 2-bromobenzoic acid compound according to claim 1, characterized in that: In step (1), T1 is -45 to -20°C, and T2 is 20 to 35°C.

5. The method for synthesizing the polyhalogen-substituted fluorine-containing 2-bromobenzoic acid compound according to claim 1, characterized in that: In step (1), the solvent 1 is selected from one or more of tetrahydrofuran, diethyl ether, and N-methylpyrrolidone; and / or the lithium reagent is n-butyllithium; And / or the mass volume ratio of the compound 1 to the solvent 1 is 1 g: 3 to 20 mL.

6. The method for synthesizing the polyhalogen-substituted fluorine-containing 2-bromobenzoic acid compound according to claim 1, characterized in that: In step (1), the molar ratio of the compound 1, diisopropylamine, 2,2,6,6-tetramethylpiperidine and lithium reagent is 1:1-1.5:0.5-1.0:1.0-1.5; and / or the mass ratio of the compound 1 to dry ice is 1:1-2.

7. The method for synthesizing the polyhalogen-substituted fluorine-containing 2-bromobenzoic acid compound according to claim 1, characterized in that: In step (2), the solvent 2 is selected from one or more of ethyl acetate, dichloromethane, and dichloroethane; And / or the mass volume ratio of the compound 1 to the solvent 2 is 1 g: 5 to 50 mL.

8. The method for synthesizing the polyhalogen-substituted fluorine-containing 2-bromobenzoic acid compound according to claim 1, characterized in that: In step (2), the alkali solution is an aqueous solution of one selected from sodium hydroxide, sodium carbonate, and sodium bicarbonate with a concentration of 0.5 to 2.0 mol; and / or the pH of the reaction system is 11 after the alkali solution is added.

9. The method for synthesizing the polyhalogen-substituted fluorine-containing 2-bromobenzoic acid compound according to claim 1, characterized in that: In step (2), the strong acid solution is an aqueous solution of hydrochloric acid or sulfuric acid with a concentration of 1.0 to 2.0 mol; and / or the pH of the reaction system is 2 after the acid solution is added.

10. The method for synthesizing the polyhalogen-substituted fluorine-containing 2-bromobenzoic acid compound according to claim 1, characterized in that: In step (1), T1 is -30°C; And / or in step (1), the molar ratio of compound 1, diisopropylamine, 2,2,6,6-tetramethylpiperidine and lithium reagent is 1:1.2:0.6:1.05; And / or in step (1), the mass ratio of the compound 1 to dry ice is 1:2; And / or in step (1), after adding diisopropylamine, keep warm and stir for 0.5h, after adding 2,2,6,6-tetramethylpiperidine, keep warm and stir for 0.5h, after adding lithium reagent, keep warm and stir for 1h, after adding compound 1, keep warm and stir for 1h, and keep warm and react for 2h after rising to T2; In step (2), the alkali solution is a 1.0 mol sodium hydroxide aqueous solution; And / or in step (2), the strong acid solution is a 1 mol hydrochloric acid aqueous solution.

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