Synthesis process of 2-bromo-5-methoxybenzoic acid

Abstract

The present invention relates to a synthesis process of 2-bromo-5-methoxybenzoic acid represented by formula (1). The method comprises carrying out a bromination reaction on 3-methoxybenzoic acid at the C-2 position in an organic acid solution in the presence of an alkali metal bromide and a bromate to synthesize the 2-bromo-5-methoxybenzoic acid compound. The method has high selectivity, simple post-treatment, high yield and purity of the product, opens up a new synthetic route and method for synthesizing 2-bromo-5-methoxybenzoic acid, and has good application potential and research value.

Description

Technical Field

[0001] The present invention belongs to the field of organic chemical synthesis, and relates to a synthesis process of bromoaromatic compounds, and more specifically to a synthesis process of 2-bromo-5-methoxybenzoic acid. Background Art

[0002] The importance of aryl halides as precursors for various functional group transformations makes the synthesis and preparation of such compounds of profound significance. As an important part of aryl halides, bromoarenes are widely used in the synthesis reactions of important organic compounds such as natural products, drugs, dyes, and polymer materials.

[0003] The reactions involving bromoarenes are mainly divided into two types: ① Bromoarenes react with metals (such as magnesium or lithium) to be converted into organometallic compounds, and then react with other various compounds to synthesize the desired target compounds; ② Under the catalysis of transition metals, they undergo coupling reactions with different substrates, such as cross-coupling reactions like Heck, Stille, Negishi, Ullmann, Kumada, Sonogashira, Suzuki, and Buchwald-Hartwig, which are widely used in the construction reactions of C-C bonds, C-O bonds, C-N bonds, and other carbon-heteroatom bonds.

[0004] The synthesis methods of bromoarenes can be further divided into direct bromination and indirect bromination. Compared with various indirect preparation methods, direct bromination of arenes is more commonly used due to its shorter steps. However, achieving mono-bromination and regioselectivity of the aromatic ring is still challenging. Especially for highly activated aromatic substrates such as phenols and their derivatives, many selective mono-bromination reagents have been reported, including liquid bromine, N-bromosuccinimide, dibromohydantoin, pyridinium tribromide, tetrabutylammonium tribromide, tetrapropylammonium nonabromide, 1-butyl-3-methylimidazolium tribromide, potassium tribromide 18-crown-6 complex, hexamethylenetetramine-bromine complex, and DABCO-derived bromine complex, etc. Although these reagents have achieved the goal of regioselective bromination in research, they still have the disadvantages of high price and inconvenient use. As one of many bromination substrates, 3-methoxybenzoic acid still faces challenges in the selective bromination at the para position of the methoxy group to synthesize 2-bromo-5-methoxybenzoic acid and realizing its industrialization. 2-Bromo-5-methoxybenzoic acid is an intermediate for synthesizing more complex drugs and bioactive compounds such as urolithin A and daludorexan.

[0005] Weimar, C. et al. (Arch. Pharm. 1991, 324, 509) disclosed a synthesis process of 2-bromo-5-methoxybenzoic acid, using liquid bromine as the bromination reagent, water as the solvent, and carrying out the bromination reaction selectively at the para position of the methoxy group in the presence of sodium hydroxide.

[0006] Cozza, G. et al. (Chem. Med. Chem. 2011, 6, 2273) and CN 106831397 disclose the synthesis process of 2-bromo-5-methoxybenzoic acid. Using liquid bromine as the bromination reagent and acetic acid as the solvent, bromination reaction is selectively carried out at the para-position of the methoxy group.

[0007] Wu, Y.-Q. et al. (Synth. Commun. 2020, 50, 813) disclose the synthesis process of 2-bromo-5-methoxybenzoic acid using NBS as the bromine source.

[0008] CN112250562 discloses a synthesis process of 2-bromo-5-methoxybenzoic acid. In this synthesis process, NIS is used as the bromination reagent and dichloromethane is used as the solvent. In the presence of concentrated sulfuric acid, potassium bromide and red phosphorus, bromination of 3-methoxybenzoic acid is achieved at the para-position of the methoxy group. The reagents used in the method disclosed in CN112250562 are too complex, and a large amount of phosphorus-containing wastewater is generated, resulting in greater environmental protection pressure.

[0009] For the above reasons, due to the importance of aryl bromides, there is still a need to introduce new methods for preparing these compounds to improve selectivity, product yield, simplify operations and shorten reaction time. This is also the basis and motivation for the completion of the present invention. Summary of the Invention

[0010] In view of this, to solve many deficiencies in the existing synthesis technology, the inventors of the present invention have conducted in-depth research on the chemical synthesis process of the compound (Formula 1). After a large amount of creative work, a simple and efficient method for synthesizing 2-bromo-5-methoxybenzoic acid is provided, and industrial scale-up research has been carried out on it, with the HPLC purity reaching over 99.5%.

[0011]

[0012] To achieve the above object, the present invention is realized by adopting the following technical solutions:

[0013] The synthesis route of the present invention is as follows:

[0014]

[0015] The synthesis process of the compound 2-bromo-5-methoxybenzoic acid shown in Formula (1) includes the following steps:

[0016] (1) Bromination reaction: In an organic acid, the compound 3-methoxybenzoic acid of Formula (2), an alkali metal bromide and a bromate are sequentially added. After the reaction is completed, the reaction solution is heated to make the system completely dissolved, cooled and crystallized, and filtered to obtain the wet crude product of 2-bromo-5-methoxybenzoic acid.

[0017] (2) Purification of 2-bromo-5-methoxybenzoic acid: Add an organic solvent to the wet crude 2-bromo-5-methoxybenzoic acid obtained in step (1), stir and heat to 50 - 70 °C. After complete dissolution, keep warm for 1 - 2 h, then slowly cool to 5 - 15 °C for crystallization for 5 - 10 h, and filter until dry; Dry to obtain pure 2-bromo-5-methoxybenzoic acid. Preferably, the synthesis process of the compound 2-bromo-5-methoxybenzoic acid shown in formula (1) includes the following steps:

[0018] Bromination reaction: After replacing the clean reaction kettle with nitrogen three times, add an organic acid to the reaction kettle, start stirring, and sequentially add 3-methoxybenzoic acid, an alkali metal bromide, and a bromate. Control the temperature in the kettle at 25 - 35 °C, stir and react for 12 h, then sample for liquid phase control (raw material ≤ 0.5%). If unqualified, continue to keep warm and react, sample and analyze every two hours until qualified; Raise the temperature of the reaction solution to 50 - 70 °C to make the system completely soluble, keep warm for 3 - 5 h. Cool to 5 - 15 °C for crystallization for 5 - 10 h, filter, wash, and filter until dry to obtain the wet crude 2-bromo-5-methoxybenzoic acid.

[0019] Purification of 2-bromo-5-methoxybenzoic acid: Weigh and transfer the wet crude 2-bromo-5-methoxybenzoic acid to a crystallization kettle, add an organic solvent, stir and heat to 50 - 70 °C. After complete dissolution, keep warm for 1 - 2 h, then slowly cool to 5 - 15 °C for crystallization for 5 - 10 h, and filter until dry; Dry the filter cake under vacuum at -0.10 - -0.08 MPa and 60 - 70 °C for 24 h. The weight loss on drying is within 0.5%. Stop drying after passing the test, otherwise continue drying, sample and detect every hour until qualified to obtain pure 2-bromo-5-methoxybenzoic acid.

[0020] In the synthesis process of the present invention, in the bromination reaction, the organic acid is one or more of acetic acid, propionic acid, isobutyric acid, difluoroacetic acid, and trifluoroacetic acid.

[0021] Most preferably, the organic acid is trifluoroacetic acid.

[0022] In the synthesis process of the present invention, in the bromination reaction, the combination of the alkali metal bromide and the bromate is one group of LiBr / NaBrO3, LiBr / KBrO3, NaBr / NaBrO3, NaBr / KBrO3, KBr / NaBrO3, KBr / KBrO3, CsBr / NaBrO3, and CsBr / KBrO3.

[0023] Most preferably, the combination of the alkali metal bromide and the bromate is KBr / KBrO3.

[0024] In the synthesis process of the present invention, in the bromination reaction, the molar ratio of the combination of the alkali metal bromide and bromate is 1:1 to 3:1, and this range includes any sub-range therein.

[0025] In the synthesis process of the present invention, in the bromination reaction, the mass ratio of the organic acid to 3-methoxybenzoic acid is 5:1 to 10:1, and this range includes any sub-range therein.

[0026] In the synthesis process of the present invention, in the bromination reaction, the total bromine molar ratio of 3-methoxybenzoic acid to the combination of bromide and bromate is 1:1 to 1:2, and this range includes any sub-range therein.

[0027] In the synthesis process of the present invention, in the bromination reaction, the bromination temperature is 25 to 35 °C, and this range includes any sub-range therein.

[0028] In the synthesis process of the present invention, in the bromination reaction, the crystallization temperature is 5 to 15 °C, and this range includes any sub-range therein.

[0029] In the purification of 2-bromo-5-methoxybenzoic acid in the synthesis process of the present invention, the organic solvent is one or more of ethyl acetate, dichloromethane, methanol, ethanol, isopropanol, butanol, difluoroacetic acid, trifluoroacetic acid, and acetic acid.

[0030] Most preferably, the organic solvent is trifluoroacetic acid.

[0031] In the synthesis process of the present invention, the drying conditions of the product are drying under vacuum at -0.10 to -0.08 MPa and 60 to 70 °C for 24 h, and this range includes any sub-range therein.

[0032] The present invention also provides a method for preparing 3-methoxybenzoic acid of the compound of formula (2), comprising the following steps:

[0033] Add m-hydroxybenzoic acid to methanol and stir evenly; add concentrated sulfuric acid, heat up to reflux, and keep the temperature for reaction; after the reaction is completed, concentrate and distill out methanol until no liquid flows out; cool down, dropwise add an alkali solution, and after dropping, keep the temperature for reaction; heat up and keep the temperature for reaction until the end point; add water for dilution, acidify for crystallization, keep the temperature for crystallization, filter, wash, and dry to obtain m-methoxybenzoic acid.

[0034]

[0035] Among them, the mass (volume) ratio of m-methoxybenzoic acid, methanol, and concentrated sulfuric acid is 1:3:2.2; the reaction temperature is the boiling point of methanol; the lye is sodium hydroxide solution; the acidifying agent is sulfuric acid; the drying temperature is 80 °C.

[027] According to one of the embodiments, the synthesis process of the present invention includes the following steps:

[0036] After the clean reaction kettle is replaced with nitrogen three times, trifluoroacetic acid (35.00 kg) is added to the reaction kettle, stirring is started, 3-methoxybenzoic acid (3.50 kg), potassium bromide (2.01 kg), and potassium bromate (1.36 kg) are added in sequence, the temperature in the kettle is controlled at 25-35 °C, and after stirring and reacting for 12 h, a liquid-phase in-process control sample is taken (raw material ≤ 0.5%). If it is unqualified, continue the heat preservation reaction, take a sample for analysis every two hours until it is qualified; the reaction solution is heated to 50-70 °C to make the system completely dissolved, and keep warm for 3-5 h. Crystallize for 5-10 h at 5-15 °C, filter, wash, and filter to dryness to obtain the wet material of crude 2-bromo-5-methoxybenzoic acid. Weigh and transfer the wet material of crude 2-bromo-5-methoxybenzoic acid to the crystallization kettle, add trifluoroacetic acid (21.00 kg), stir and heat to 50-70 °C, keep warm for 1-2 h after complete dissolution, slowly cool to 5-15 °C for crystallization for 5-10 h, and filter to dryness; the filter cake is dried under vacuum at -0.10 to -0.08 MPa and 60-70 °C for 24 h, and the drying loss is within 0.5%. Stop drying after passing the test, otherwise continue drying, take samples for detection every hour until qualified, to obtain pure 2-bromo-5-methoxybenzoic acid, and the chromatographic purity > 99.0%.

[0037] The present invention selects 3-methoxybenzoic acid as the starting material, uses the KBr / KBrO3 combination as the bromine source, and synthesizes 2-bromo-5-methoxybenzoic acid through their common action. The method has many advantages, such as high regioselectivity, simple post-treatment, easy operation, scalable production, and high yield and purity of the product. The method of the present invention provides theoretical and technical guidance for the synthesis and production of 2-bromo-5-methoxybenzoic acid. Specific Embodiments

[0038] The present invention is further illustrated by the following specific examples, but it is not limited to the present invention.

[0039] Example 1:

[0040] After the clean reaction kettle was replaced with nitrogen three times, trifluoroacetic acid (35.00 g) was added to the reaction kettle. Stirring was started, and 3-methoxybenzoic acid (3.50 g), potassium bromide (2.01 g), and potassium bromate (1.36 g) were sequentially added. The temperature inside the kettle was controlled at 25 - 35 °C. After stirring and reacting for 12 h, a sample was taken for in-liquid control (raw materials ≤ 0.5%). If it was unqualified, the reaction was continued with heat preservation, and samples were taken for analysis every two hours until it was qualified; the reaction solution was heated to 50 - 70 °C to make the system completely dissolved, and heat preservation was carried out for 3 - 5 h. It was cooled to 5 - 15 °C for crystallization for 5 - 10 h, filtered, washed, and filtered to dryness to obtain the wet material of the crude product of 2-bromo-5-methoxybenzoic acid. The wet material of the crude product of 2-bromo-5-methoxybenzoic acid was weighed and transferred to a crystallization kettle, trifluoroacetic acid (21.00 g) was added, stirred and heated to 50 - 70 °C, after complete dissolution, heat preservation was carried out for 1 - 2 h, and it was slowly cooled to 5 - 15 °C for crystallization for 5 - 10 h, and filtered to dryness; the filter cake was dried under vacuum at -0.10 - -0.08 MPa and 60 - 70 °C for 24 h, the drying loss was within 0.5%, and drying was stopped after being qualified, otherwise, drying was continued, and samples were taken for detection every hour until it was qualified, and the pure product of 2-bromo-5-methoxybenzoic acid (white to off-white solid, 4.52 g, yield 85%, HPLC purity > 99.0%) was obtained. 1 H NMR(DMSO-d6,400MHz)δ13.41(s,1H),7.58(d,J=8.8Hz,1H),7.26(d,J=3.2Hz,1H),7.021(dd,J=8.8,2.8Hz,1H),3.78(s,3H); 13 C NMR(DMSO-d6,100MHz)δ167.2,158.4,134.6,134.6,118.5,115.6,110.1,55.7.HRMS-ESI(m / z):C8H6BrO3,calcd:[M-H] - 230.9485;found 230.9482.

[0041] Except that the trifluoroacetic acid was replaced with the following organic acids respectively, Examples 2 - 5 were respectively carried out in the same manner as in Example 1, and the organic acids used and the yields and purities of the corresponding products are shown in the following table.

[0042]

[0043]

[0044] Example 6:

[0045] After the clean reaction kettle is purged with nitrogen three times, trifluoroacetic acid (35.00 g) is added to the reaction kettle. Stirring is started, and 3-methoxybenzoic acid (3.50 g), potassium bromide (2.01 g), and potassium bromate (1.36 g) are added in sequence. The temperature inside the kettle is controlled at 25-35 °C. After stirring and reacting for 12 h, a sample is taken for in-process liquid-phase control (raw materials ≤ 0.5%). If it is unqualified, continue the insulation reaction, and take a sample for analysis every two hours until it is qualified; the reaction solution is heated to 50-70 °C to make the system completely dissolved, and keep warm for 3-5 h. Crystallize for 5-10 h under the condition of cooling to 5-15 °C, filter, wash, and filter until dry to obtain the wet material of the crude product of 2-bromo-5-methoxybenzoic acid. Weigh and transfer the wet material of the crude product of 2-bromo-5-methoxybenzoic acid to the crystallization kettle, add trifluoroacetic acid (17.5 g), stir and heat to 50-70 °C, keep warm for 1-2 h after complete dissolution, slowly cool to 5-15 °C for crystallization for 5-10 h, and filter until dry; the filter cake is dried under vacuum at -0.10 to -0.08 MPa and 60-70 °C for 24 h. The drying loss is within 0.5%. Stop drying after it is qualified, otherwise continue drying, and take a sample for detection every hour until it is qualified to obtain the pure product of 2-bromo-5-methoxybenzoic acid (white to off-white solid, 4.71 g, yield 88.6%, HPLC purity 98.5%).

[0046] Example 7:

[0047] After the clean reaction kettle is purged with nitrogen three times, trifluoroacetic acid (35.00 g) is added to the reaction kettle. Stirring is started, and 3-methoxybenzoic acid (3.50 g), potassium bromide (2.01 g), and potassium bromate (1.36 g) are added in sequence. The temperature inside the kettle is controlled at 25-35 °C. After stirring and reacting for 12 h, a sample is taken for in-process liquid-phase control (raw materials ≤ 0.5%). If it is unqualified, continue the insulation reaction, and take a sample for analysis every two hours until it is qualified; the reaction solution is heated to 50-70 °C to make the system completely dissolved, and keep warm for 3-5 h. Crystallize for 5-10 h under the condition of cooling to 5-15 °C, filter, wash, and filter until dry to obtain the wet material of the crude product of 2-bromo-5-methoxybenzoic acid. Weigh and transfer the wet material of the crude product of 2-bromo-5-methoxybenzoic acid to the crystallization kettle, add trifluoroacetic acid (35.0 g), stir and heat to 50-70 °C, keep warm for 1-2 h after complete dissolution, slowly cool to 5-15 °C for crystallization for 5-10 h, and filter until dry; the filter cake is dried under vacuum at -0.10 to -0.08 MPa and 60-70 °C for 24 h. The drying loss is within 0.5%. Stop drying after it is qualified, otherwise continue drying, and take a sample for detection every hour until it is qualified to obtain the pure product of 2-bromo-5-methoxybenzoic acid (white to off-white solid, 3.95 g, yield 74.2%, HPLC purity > 99.0%).

[0048] Examples 8 - 14 were carried out in the same manner (same molar ratio) as in Example 1, except that the KBr / KBrO3 combination was replaced with the following bromine source combinations respectively. The bromine source combinations used, and the yields and purities of the corresponding products are shown in the following table.

[0049]

[0050] Example 15

[0051] After the clean reaction kettle was purged with nitrogen three times, trifluoroacetic acid (35.00 g) was added to the reaction kettle, and stirring was started. 3-Methoxybenzoic acid (3.50 g), potassium bromide (2.01 g), and potassium bromate (2.82 g) were added in sequence. The temperature in the kettle was controlled at 25 - 35 °C, and after stirring and reacting for 12 h, a sample was taken for in - liquid control (raw materials ≤ 0.5%). If unqualified, continue to keep the temperature for reaction, and take samples for analysis every two hours until qualified; the reaction solution was heated to 50 - 70 °C to make the system completely dissolved, and kept warm for 3 - 5 h. It was cooled to 5 - 15 °C for crystallization for 5 - 10 h, filtered, washed, and filtered to dryness to obtain the wet crude product of 2 - bromo - 5 - methoxybenzoic acid. The wet crude product of 2 - bromo - 5 - methoxybenzoic acid was weighed and transferred to a crystallization kettle, trifluoroacetic acid (21.00 g) was added, stirred and heated to 50 - 70 °C, and after complete dissolution, it was kept warm for 1 - 2 h, and slowly cooled to 5 - 15 °C for crystallization for 5 - 10 h, and filtered to dryness; the filter cake was dried under vacuum at - 0.10 - - 0.08 MPa and 60 - 70 °C for 24 h, and the weight loss on drying was within 0.5%. After passing the test, stop drying, otherwise continue drying, and take samples for detection every hour until qualified, to obtain the pure product of 2 - bromo - 5 - methoxybenzoic acid (white to off - white solid, 4.23 g, yield 79.5%, HPLC purity > 99.0%).

[0052] Example 16

[0053] After the clean reaction kettle is replaced with nitrogen three times, trifluoroacetic acid (35.00 g) is added to the reaction kettle, the stirring is started, and 3-methoxybenzoic acid (3.50 g), potassium bromide (3.02 g) and potassium bromate (1.36 g) are added in sequence. The temperature in the kettle is controlled at 25-35 °C, and after stirring and reacting for 12 h, a sample is taken for liquid-phase in-process control (raw materials ≤ 0.5%). If it is unqualified, continue the heat preservation reaction, and take a sample for analysis every two hours until it is qualified; the reaction solution is heated to 50-70 °C to make the system completely dissolved, and heat preservation is carried out for 3-5 h. Crystallize at 5-15 °C for 5-10 h, filter, wash, and filter until dry to obtain the wet material of the crude product of 2-bromo-5-methoxybenzoic acid. Weigh the wet material of the crude product of 2-bromo-5-methoxybenzoic acid and transfer it to the crystallization kettle, add trifluoroacetic acid (21.00 g), stir and heat to 50-70 °C, keep warm for 1-2 h after complete dissolution, slowly cool to 5-15 °C to crystallize for 5-10 h, and filter until dry; the filter cake is dried under vacuum at -0.10 to -0.08 MPa and 60-70 °C for 24 h, and the drying loss is within 0.5%. Stop drying after qualification, otherwise continue drying, and take a sample for detection every hour until qualified to obtain the pure product of 2-bromo-5-methoxybenzoic acid (white to off-white solid, 4.42 g, yield 83%, HPLC purity > 99.0%).

[0054] Example 17

[0055] After the clean reaction kettle is replaced with nitrogen three times, trifluoroacetic acid (35.00 g) is added to the reaction kettle, the stirring is started, and 3-methoxybenzoic acid (3.50 g), potassium bromide (4.02 g) and potassium bromate (2.72 g) are added in sequence. The temperature in the kettle is controlled at 25-35 °C, and after stirring and reacting for 12 h, a sample is taken for liquid-phase in-process control (raw materials ≤ 0.5%). If it is unqualified, continue the heat preservation reaction, and take a sample for analysis every two hours until it is qualified; the reaction solution is heated to 50-70 °C to make the system completely dissolved, and heat preservation is carried out for 3-5 h. Crystallize at 5-15 °C for 5-10 h, filter, wash, and filter until dry to obtain the wet material of the crude product of 2-bromo-5-methoxybenzoic acid. Weigh the wet material of the crude product of 2-bromo-5-methoxybenzoic acid and transfer it to the crystallization kettle, add trifluoroacetic acid (35.0 g), stir and heat to 50-70 °C, keep warm for 1-2 h after complete dissolution, slowly cool to 5-15 °C to crystallize for 5-10 h, and filter until dry; the filter cake is dried under vacuum at -0.10 to -0.08 MPa and 60-70 °C for 24 h, and the drying loss is within 0.5%. Stop drying after qualification, otherwise continue drying, and take a sample for detection every hour until qualified to obtain the pure product of 2-bromo-5-methoxybenzoic acid (white to off-white solid, 4.76 g, yield 89.5%, HPLC purity 98.4%).

[0056] Examples 18 - 25 were respectively implemented in the same manner as in Example 1, except that trifluoroacetic acid was replaced with the following organic solvents respectively. The organic solvents used and the yields and purities of the corresponding products are shown in the following table.

[0057]

[0058]

[0059] Example 26

[0060] After the clean reaction kettle was replaced with nitrogen three times, trifluoroacetic acid (35.00 kg) was added to the reaction kettle, stirring was started, and 3 - methoxybenzoic acid (3.50 kg), potassium bromide (2.01 kg), and potassium bromate (1.36 kg) were added in sequence. The temperature in the kettle was controlled at 25 - 35 °C, and after stirring and reacting for 12 h, a sample was taken for liquid - phase in - process control (raw material ≤ 0.5%). If it was unqualified, the reaction was continued with heat preservation, and a sample was taken for analysis every two hours until it was qualified; the reaction solution was heated to 50 - 70 °C to make the system completely soluble, and heat - preserved for 3 - 5 h. It was cooled to 5 - 15 °C for crystallization for 5 - 10 h, filtered, washed, and filtered to dryness to obtain the wet material of crude 2 - bromo - 5 - methoxybenzoic acid. The wet material of crude 2 - bromo - 5 - methoxybenzoic acid was weighed and transferred to the crystallization kettle, trifluoroacetic acid (21.00 kg) was added, stirred and heated to 50 - 70 °C, after complete dissolution, it was heat - preserved for 1 - 2 h, and slowly cooled to 5 - 15 °C for crystallization for 5 - 10 h, filtered to dryness; the filter cake was dried under vacuum at - 0.10 - - 0.08 MPa and 60 - 70 °C for 24 h. The drying loss was within 0.5%. After passing the test, the drying was stopped, otherwise, the drying was continued, and samples were taken for detection every hour until it was qualified, to obtain pure 2 - bromo - 5 - methoxybenzoic acid (white to off - white solid, 4.75 kg, yield 89%, HPLC purity > 99.0%).

[0061] Example 27

[0062] Methanol (150 mL) and m - hydroxybenzoic acid (50 g) were successively added to a clean reaction kettle, stirring was started, concentrated sulfuric acid (110 g) was added dropwise, and after the addition was completed, the temperature was raised to reflux and heat - preserved for 12 h; after the reaction was completed, methanol was concentrated and distilled until no liquid flowed out; the temperature was lowered to 25 - 30 °C, and 30% sodium hydroxide solution was added dropwise. After the addition was completed, it was heat - preserved for 8 h; the temperature was raised to 70 - 80 °C and heat - preserved until the end; water was added for dilution, and sulfuric acid was used for acidification to crystallize. The temperature was lowered to 10 - 15 °C and heat - preserved for crystallization for 5 h, filtered, washed, and dried under vacuum at 80 °C to obtain m - methoxybenzoic acid (47.4 g, yield 86%).

[0063] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it based on the present invention, which are obvious to those skilled in the art. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection required by the present invention.

Claims

1. A synthetic process of 2-bromo-5-methoxybenzoic acid, wherein the 2-bromo-5-methoxybenzoic acid is the compound shown in formula (1), characterized in that, It includes the following steps: (1) Bromination reaction: In trifluoroacetic acid, sequentially add the compound 3-methoxybenzoic acid of formula (2), an alkali metal bromide, and a bromate. After the reaction is completed, raise the temperature of the reaction solution to make the system completely dissolved, cool and crystallize, and filter to obtain the wet crude product of 2-bromo-5-methoxybenzoic acid; The alkali metal of the alkali metal bromide is selected from Li, Na, K, Cs; the RCO2H is trifluoroacetic acid; (2) Refinement of 2-bromo-5-methoxybenzoic acid: Add trifluoroacetic acid to the wet crude product of 2-bromo-5-methoxybenzoic acid obtained in step (1), stir and heat to 50-70 °C, keep warm for 1-2 h after complete dissolution, slowly cool to 5-15 °C for crystallization for 5-10 h, and filter to dryness; Dry to obtain pure 2-bromo-5-methoxybenzoic acid; Among them, the molar ratio of the combination of the alkali metal bromide and the bromate in step (1) is 1:1 to 3:1; the mass ratio of trifluoroacetic acid to 3-methoxybenzoic acid is 5:1 to 10:1; the total bromine molar ratio of 3-methoxybenzoic acid to the combination of the bromide and the bromate is 1:1 to 1:2; The preparation method of the compound 3-methoxybenzoic acid of formula (2) includes the following steps: Add m-hydroxybenzoic acid to methanol, stir evenly; add concentrated sulfuric acid, raise the temperature to reflux, and keep the reaction warm; after the reaction is completed, concentrate and distill off methanol until no liquid flows out; cool down, dropwise add NaOH solution, and keep the reaction warm after dropping; raise the temperature and keep the reaction warm until the end point; add water for dilution, acidify and crystallize, keep the temperature for crystallization, filter, wash, and dry to obtain m-methoxybenzoic acid.

2. The synthesis process according to claim 1, characterized in that: Before adding trifluoroacetic acid in the bromination reaction of step (1), replace the reaction kettle with nitrogen three times.

3. The synthesis process according to claim 1, characterized in that: The combination of the alkali metal bromide and the bromate in step (1) is one of LiBr / NaBrO3, LiBr / KBrO3, NaBr / NaBrO3, NaBr / KBrO3, KBr / NaBrO3, KBr / KBrO3, CsBr / NaBrO3 or CsBr / KBrO3.

4. The synthesis process according to claim 1, characterized in that, In step (1), the bromination temperature is 25-35 °C; the temperature for heating and dissolution is 50-70 °C, and keep warm for 3-5 h; the crystallization temperature is 5-15 °C, and the crystallization time is 5-10 h.

5. The synthesis process according to claim 1, characterized in that, The drying conditions of the product in step (2) are drying under vacuum at -0.10 to -0.08 MPa and 60-70 °C for 24 h, and the drying loss is within 0.5%.

6. The synthesis process according to claim 1, wherein The mass and volume ratio of m-hydroxybenzoic acid, methanol, and concentrated sulfuric acid is 1 g:3 ml:2.2 g; the reaction temperature is the boiling point of methanol; the alkali solution is sodium hydroxide solution; the acidifying agent is sulfuric acid; the drying temperature is 80 °C.

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