A method for synthesizing 2,2'-diphenyldicarboxylic acid compounds

Abstract

The application discloses a synthesis method of 2,2'-biphenyldicarboxylic acid compounds, which comprises the following steps: carrying out a reduction coupling reaction on a halogenated benzoic acid compound and a metal reducing agent under the action of an alkali and a nickel catalyst / bidentate ligand composite catalyst system to obtain the 2,2'-biphenyldicarboxylic acid compound. The method uses 2-halogenated benzoic acid compounds as raw materials, and can obtain the 2,2'-biphenyldicarboxylic acid compounds in a high yield through one-pot reaction catalyzed by a transition metal Ni. The method has the advantages of low cost, mild reaction condition, simple reaction operation, high ortho-regioselectivity, avoidance of unnecessary derivatization steps, fast and efficient coupling reaction and the like, and has high industrial production value.

Description

Technical Field

[0001] This invention relates to a method for synthesizing 2,2'-biphenyl dicarboxylic acid compounds, specifically a method for synthesizing 2,2'-biphenyl dicarboxylic acid compounds by reductive coupling reaction of nickel-catalyzed halobenzoic acid compounds, belonging to the field of organic synthesis technology. Background Technology

[0002] With the development of science and technology, organic chemists have discovered an increasing number of organic synthesis methods catalyzed by transition metals. The establishment of transition metal catalytic cycles to construct coupling reactions of CC, CN, CS, and CB chemical bonds has greatly promoted the development of organometallic chemistry. The classic Ullmann reaction is a Cu-catalyzed coupling reaction of aryl halides; however, due to the stringent reaction conditions required for Cu catalysis—generally requiring temperatures above 100 degrees Celsius—the yields are typically low, posing a significant risk for large-scale industrial production.

[0003] Currently, 2,2'-biphenyl dicarboxylic acid and its derivatives play an increasingly important role in pharmaceutical synthesis, luminescent materials, liquid crystal materials, and porous materials, but efficient, rapid, and convenient synthetic methods are lacking. 2,2'-biphenyl dicarboxylic acid and its derivatives are important intermediates in pharmaceutical synthesis. As intermediates, they can undergo further functional group transformations, being reduced to the corresponding aldehydes and alcohols, or undergoing condensation reactions with some alcohols and amines to obtain the next product.

[0004] Currently, there are several methods for synthesizing 2,2'-biphenyl dicarboxylic acid and its derivatives:

[0005]

[0006] Chen, Zhicai, and others first used a transition metal Pd catalyst to perform a C-C cross-coupling reaction between 2-bromotoluene and methyl 2-bromo-3-methylbenzoate, yielding a 90% coupling product. The ester bond in the coupling product was then hydrolyzed under alkaline conditions, yielding a 96% hydrolysate. Finally, potassium permanganate was used to directly oxidize the methyl group to a carboxyl group, yielding the 2,2'-biphenyl dicarboxylic acid derivative. While this method achieved yields above 90% at each step, it had several drawbacks. First, the process to obtain 2,2'-biphenyl dicarboxylic acid involved numerous unnecessary derivatization steps, making it unsuitable for scale-up production. Second, the coupling and oxidation reactions involved relatively high temperatures, posing a risk for scale-up. Finally, the use of the noble metal Pd reduced its industrial viability.

[0007]

[0008] Saphier, Magal, and others used 2-bromobenzoic acid as a substrate to catalyze the formation of 2,2'-biphenyldicarboxylic acid with Cu salts. They also used this model to investigate in detail the mechanism of transition metal Cu salt-catalyzed product formation and various influencing factors. The advantage of this reaction is that it allows for a direct one-step yield of 2,2'-biphenyldicarboxylic acid from 2-bromobenzoic acid. However, this reaction model also produces benzoic acid and acetylsalicylic acid as byproducts, and the yield of 2,2'-biphenyldicarboxylic acid is relatively low, making it unsuitable for industrial-scale production. In fact, direct production would result in a low overall yield.

[0009]

[0010] Zeng, Zhongyi, and others used 2-methylbenzoic acid as a template substrate, the noble metal Rh as a metal catalyst, inert electrodes Pt as positive and negative electrodes respectively, tetrabutylammonium acetate as an additive, and DMF as a solvent to react for 20 hours under a 1.0 mA current to obtain 2,2'-biphenyl dicarboxylic acid derivatives. This reaction can directly and directly yield 2,2'-biphenyl dicarboxylic acid derivatives in one step via transition metal Rh catalysis, with a yield of 87%. However, it has many drawbacks for industrial scale-up. First, it requires an electric current, consuming significant electrical resources; second, it requires the noble metal Rh; and finally, the reaction time is relatively long, making industrial-scale production too costly. These factors make this reaction impractical for industrial production.

[0011]

[0012] Murai, Takuya, and others used methyl 2-bromobenzoate as the starting material and Cu as the catalyst in DMF under reflux to first obtain methyl 2,2'-biphenyldicarboxylate. Subsequently, hydrolysis under alkaline conditions with NaOH in THF / MeOH / H2O solvent yielded 2,2'-biphenyldicarboxylic acid and its derivatives. This synthetic route achieves an overall yield greater than 90%, but the carboxyl group needs to be protected by an ester bond before the coupling reaction can proceed; it cannot directly couple to obtain 2,2'-biphenyldicarboxylic acid and its derivatives, adding two steps of protection and deprotection. The Ullmann coupling reaction requires very harsh conditions, including reflux in DMF, which poses a significant risk to industrial scale-up. Therefore, this synthetic route is not suitable for industrial application. A method is needed that uses the cheapest reagents, operates under mild conditions, has high functional group tolerance, and can directly yield 2,2'-biphenyldicarboxylic acid and its derivatives in one step.

[0013] In recent years, reductive coupling reactions catalyzed by transition metal Ni have been gradually developed. Firstly, Ni is used as the catalyst instead of noble metals such as Pd and Rh, significantly reducing costs. Various coupling reactions can typically occur directly using halides, such as direct coupling of C-C, C-S, and C-N bonds. These reactions can be carried out under relatively mild conditions, without the harsh conditions required for the Ullmann reaction (reflux under DMF conditions). Secondly, the starting materials are inexpensive and readily available; alkyl halides are usually commercially available, further reducing costs and eliminating the need for unnecessary deprotection steps. In summary, reductive coupling reactions catalyzed by transition metal Ni offer advantages such as low reaction cost, mild reaction conditions, and efficient, rapid, and direct coupling, making them highly valuable for industrial application.

[0014] In summary, existing technologies lack methods for the direct industrial-scale synthesis of 2,2'-biphenyl dicarboxylic acid and its derivatives, mainly for the following reasons:

[0015] 1. The classic Ullmann reaction typically uses metallic Cu or Cu salts as catalysts and amide solvents such as DMF, and is carried out under reflux conditions. Since the boiling points of various amide solvents are all above 100°C, the risks of industrial scale-up are extremely high, making this reaction unsuitable for large-scale production.

[0016] 2. In the background literature above, the synthesis of 2,2'-biphenyldicarboxylic acid and its derivatives requires the protection of the carboxyl group, for example, by protecting it to an ester group before carrying out a transition metal-catalyzed coupling reaction, followed by deprotection of the ester group under basic conditions to obtain the carboxyl group. This adds two extra steps of protection and deprotection to obtain the product, resulting in many unnecessary derivatization steps, poor atom economy, and making this reaction unsuitable for direct industrial-scale production.

[0017] 3. The synthesis of 2,2'-biphenyl dicarboxylic acid and its derivatives sometimes requires the use of precious metals such as Pd and Rh, which greatly increases the cost of synthesis. The raw materials are uneconomical, readily available, and expensive. Using Cu as a transition metal catalyst results in low yields of the target product and is also hazardous, so it is not suitable for direct scale-up production.

[0018] 4. The reactions catalyzed by the above transition metals generally take a long time – typically 20 hours, as reported in the literature. Therefore, efficient synthetic methods are needed to rapidly obtain the target product in a short time, while also achieving a considerable yield.

[0019] 5. For 2,4-dibromobenzoic acid, the regioselectivity of transition metals such as Cu and Pd as catalysts is not high, resulting in the formation of not only 2,2'-biphenyldicarboxylic acid but also 4,4'-biphenyldicarboxylic acid as a byproduct. Such regulation requires the addition of additives to achieve regioselectivity control, specifically generating 2,2'-biphenyldicarboxylic acid and its derivatives. Summary of the Invention

[0020] To address the shortcomings of existing technologies, the present invention aims to provide a simple and efficient method for synthesizing 2,2'-biphenyl dicarboxylic acid compounds. This method uses 2-halobenzoic acid compounds as raw materials and conducts a one-pot reaction catalyzed by transition metal Ni, which can obtain 2,2'-biphenyl dicarboxylic acid compounds in high yield. Moreover, this method is low in cost, has mild reaction conditions, is simple to operate, has high ortho-regioselectivity, and avoids unnecessary derivatization steps, coupling reactions, and other problems, making it of high industrial production value.

[0021] To achieve the above-mentioned technical objectives, the present invention provides a method for synthesizing 2,2'-biphenyl dicarboxylic acid compounds. The method involves a reductive coupling reaction between a halobenzoic acid compound and a metal reducing agent under the action of an alkaline and nickel catalyst / bident ligand composite catalytic system to obtain 2,2'-biphenyl dicarboxylic acid compounds.

[0022] The halobenzoic acid compounds have the structure of Formula 1:

[0023]

[0024] The 2,2'-biphenyl dicarboxylic acid compounds have the structure of Formula 2:

[0025]

[0026] in,

[0027] X is a halogen substituent;

[0028] R1 and R2 are independently selected from hydrogen and C. 1～10 aliphatic groups, C 1～10 Aliphatic derivative groups, C 1～10 Aliphatic ether groups, C 1～10 Aliphatic ether derivative groups, halogen substituents, C 2～10 Ester groups, sulfonic acid groups, silane ether groups, or amide groups.

[0029] In the halobenzoic acid compounds of the present invention, X is a substituent that is easily eliminated, such as a halogen substituent. The halogen substituent can generally be a chlorine substituent, a bromine substituent, or an iodine substituent, while X is generally not a fluorine substituent with lower activity.

[0030] The halobenzoic acid compounds and 2,2'-biphenyl dicarboxylic acid compounds of the present invention both contain R1 and R2 groups, where R1 and R2 are substituent groups on the benzene ring. The choice of different substituent groups R1 and R2 has a certain influence on the reductive coupling reaction of the halobenzoic acid compounds, but generally speaking, R1 and R2 are independently selected from hydrogen and C. 1～10 aliphatic groups, C 1～10 Aliphatic derivative groups, C 1～10 Aliphatic ether groups, C 1～10 Aliphatic ether derivative groups, halogen substituents, C 2～10 When ester groups, sulfonic acid groups, silane ether groups, or amide groups are used, the yield of the target product of 2,2'-biphenyl dicarboxylic acid compounds is in the range of 59% to 95%, which is relatively high compared to existing one-pot synthesis methods. The substitution positions of R1 and R2 on the benzene ring are not restricted. R1 and R2 are selected from C1 and C2. 1～10 When aliphatic groups are used, the aliphatic groups can be C1 to C2. 10 The alkyl group can be a straight-chain alkyl group, and when it has more than 3 carbon atoms, it can also be a branched alkyl group or a cycloalkyl group, such as methyl, propyl, cyclohexyl, isobutyl, etc.; the aliphatic group can also be C2 to C3. 10 The unsaturated aliphatic groups containing alkenyl and / or ynyl groups can be one or more, and their positions are not limited. R1 and R2 are selected from C. 1～10 When aliphatic derivative groups are used, they are at C 1～10 The aliphatic group further contains some common substituents, such as hydroxyl, cyano, halogen substituents, and other common small molecule substituents. R1 and R2 are selected from C. 1～10 When aliphatic ether groups are used, these groups can be alkoxy groups, alkenyl groups, or alkynyl groups. The alkyl group in the alkoxy group can be a straight-chain alkyl group; if it has more than 3 carbon atoms, it can also be a branched alkyl group or a cycloalkyl group, such as methyl, propyl, cyclohexyl, isobutyl, etc. The number and position of alkenyl and / or alkynyl groups in the aliphatic ether group can be one or more, and their positions are not limited. R1 and R2 are selected from C... 1～10 When aliphatic ether derivative groups are used, they are at C 1～10 The aliphatic ether group further contains some common substituents, such as hydroxyl, cyano, halogen substituents, and other common small molecule substituents. When R1 and R2 are selected from halogen substituents, the halogen substituent can be fluorine or chlorine, and its reactivity must be lower than that of the halogen substituent ortho-position to the carboxyl group. For example, when chlorine is selected as the substituent ortho-position to the carboxyl group, it is best to choose fluorine, which has lower reactivity. R1 and R2 are selected from C 2～10 When ester groups are involved, for example: The choice of R is very broad. It can be a saturated or unsaturated aliphatic hydrocarbon group, an aromatic hydrocarbon group, or a group derived from saturated, unsaturated, or aromatic hydrocarbon groups. For example, conventional substituents such as halogens, ether chains, and trifluoromethyl groups can be introduced onto these groups, specifically methoxyacyl and trifluoromethoxyacyl groups. When R1 and R2 are selected from sulfonic acid groups, such as methanesulfonate esters. When R1 and R2 are selected from silane ether groups, such as TBDMS. When R1 and R2 are selected from amide groups, such as... R3 can be a saturated aliphatic hydrocarbon group or an unsaturated aliphatic hydrocarbon group, or an aromatic hydrocarbon group, or a group derived from a saturated aliphatic hydrocarbon group, an unsaturated aliphatic hydrocarbon group, an aromatic hydrocarbon group, etc. For example, conventional substituents such as halogens, ether chains, trifluoromethyl groups, etc. are introduced onto these groups, such as isopropyl, cyclohexyl, isobutyl, etc.

[0031] As a preferred embodiment, the halogenated benzoic acid compound is 2-iodobenzoic acid, 2-bromo-4-methylbenzoic acid, 2-bromo-4-tert-butylbenzoic acid, 2-bromo-4-methoxybenzoic acid, 2-bromo-4,5-difluorobenzoic acid, 2-bromo-5-fluorobenzoic acid, 2-chlorobenzoic acid, 2-bromo-6-(trifluoromethoxy)benzoic acid, 2-bromo-4-trifluoromethylbenzoic acid, 2-bromo-4-cyanobenzoic acid, 2-iodo-5-methylbenzoic acid, 2-iodo-5-methoxybenzoic acid, 2-iodo-5-fluorobenzoic acid, 2-iodo-4,5-dimethoxytoluic acid, 5-chloro- 2-Iodobenzoic acid, 2-iodo-5-trifluoromethylbenzoic acid, 2-iodo-4,5-difluorobenzoic acid, 2-bromo-5-methoxybenzoic acid, 2-chloro-5-methoxybenzoic acid, 2-chloro-5-(methylthio)benzoic acid, 2-chloro-6-fluorobenzoic acid, 2-chloro-5-methylbenzoic acid, 2-chloro-4-methylsulfonylbenzoic acid, 2-chloro-6-(trifluoromethyl)benzoic acid, 2-bromo-4-fluoro-5-methylbenzoic acid, 6-bromo-2-fluoro-3-trifluoromethylbenzoic acid, 2-bromo-4-fluoro-5-methoxybenzoic acid, 2-bromo-3-methylbenzoic acid, 2-chloro-3-methyl 2-Bromo-3-methoxybenzoic acid, 2-Bromo-6-fluoro-3-methylbenzoic acid, 3-Bromothiophene-2-carboxylic acid, 2-Bromo-5-((tert-butyldimethylsilyl)oxy)benzoic acid, 2-Bromo-5-((triisopropylsilyl)oxy)benzoic acid, 2-Bromo-5-butoxybenzoic acid, 2-Bromo-5-(isopentoxy)benzoic acid, 2-Bromo-5-(2-ethylbutoxy)benzoic acid, 2-Bromo-5-(cyclopropylmethoxy)benzoic acid, 2-Bromo-5-(cyclobutylmethoxy)benzoic acid, 2-Bromo-5- (cyclohexylmethoxy)benzoic acid, 2-bromo-5-(3-methoxypropoxy)benzoic acid, 2-bromo-5-((4-methylpent-3-en-1-yl)oxy)benzoic acid, 2-bromo-5-(4,4,4-trifluorobutoxy)benzoic acid, 2-bromo-5-(3-cyanopropoxy)benzoic acid, 2-bromo-5-(4-methylpentamido)benzoic acid, 2-bromo-5-(2-ethoxyacetamito)benzoic acid, 2-bromo-5-isobutamidobenzoic acid, 2-bromo-5-(cyclopentanecarboxamide)benzoic acid, or 2-bromo-4-((tert-butoxycarbonyl)amino)benzoic acid.

[0032] As a preferred embodiment, the nickel catalyst comprises at least one of nickel dibromide, nickel dichloride, nickel diiodide, nickel carbonate, nickel citrate, nickel oxalate, nickel acetylacetonate, nickel formate, nickel acetate, nickel sulfate, nickel oxide, bis(1,5-cyclooctadiene) nickel, bis(pentamethylcyclopentadiene) nickel, bis(cyclopentadiene) nickel, tetra(triphenylphosphine) nickel, bis(triphenylphosphine) nickel dichloride, bis(triphenylphosphine) nickel dibromide, bis(triphenylphosphine) dicarbonyl nickel, dibromobis(pyridine) nickel, dichlorobis(pyridine) nickel, nickel(II) bromide diethylene glycol dimethyl ether complex, nickel(II) chloride diethylene glycol dimethyl ether complex, and dibromobis(tert-butylpyridine) nickel. Among them, the preferred materials with better effects are tetra(triphenylphosphine) nickel, bis(triphenylphosphine) nickel dichloride, bis(triphenylphosphine) nickel dibromide, nickel(II) bromide diethylene glycol dimethyl ether complex, and nickel(II) chloride diethylene glycol dimethyl ether complex.

[0033] As a preferred embodiment, the amount of nickel catalyst used is 5 to 20% of the molar amount of the halobenzoic acid compound.

[0034] As a preferred embodiment, the bidentate ligand includes at least one of bipyridine ligands, phenanthroline ligands, and oxazoline ligands. Examples include 3,4,7,8-tetramethyl-1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline, 1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 2,9-dimethyl-4,7-biphenyl-1,10-o-diazaphenanthroline, 2,2':6',2"-terpyridine, 2,9-dimethyl-1,10-phenanthroline, 4,7-dimethoxy-1,10-phenanthroline, 3,3'-dimethyl-2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, 5 5'-Dimethyl-2,2-bipyridine, 6,6'-Dimethyl-2,2-bipyridine, 4,4'-Dimethoxy-2,2'-bipyridine, 4,4'-Di-tert-butyl-2,2'-bipyridine, 2,2'-bipyridine, 2,2-bis(2-oxazoline), 2,6-bis[(4R)-4-phenyl-2-oxazoline]pyridine, (S,S)-2,6-bis(4-phenyl-2-oxazoline-2-yl)pyridine, 2,6-bis[(4S)-4-benzyl-2-oxazoline-2-yl]pyridine, (S,S)-2,6-bis(4- At least one of isopropyl-2-oxazoline-2-yl)pyridine, (R,R)-2,6-bis(4-isopropyl-2-oxazoline-2-yl)pyridine, and (R,R)-2,6-bis(4-isopropyl-2-oxazoline-2-yl)pyridine is selected. Among them, 3,4,7,8-tetramethyl-1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline, 1,10-phenanthroline, and 4,7-dimethyl-1,10-phenanthroline are particularly effective. After the ligands are coordinated to the metallic Ni catalyst, the conditions for the reaction to occur are created, allowing it to better carry out the coupling reaction.

[0035] As a preferred embodiment, the amount of the bidentate ligand is 1.5 to 3 times the molar amount of the nickel catalyst. If the proportion of bidentate ligand is too high, it not only increases costs but also leads to hydrogen bonding with the substrate, reducing the reaction yield. If the proportion of bidentate ligand is too low, it may not be fully coordinated to the Ni catalyst, rendering the Ni catalyst ineffective and reducing the coupling reaction yield.

[0036] As a preferred embodiment, the metal reducing agent is at least one selected from manganese, zinc, iron, and indium. The metal reducing agent is mainly used to reduce reaction intermediates in metal-catalyzed reactions. Divalent nickel reacts with the substrate during the catalytic reaction to form an intermediate, and the metal reducing agent reduces divalent nickel to zero-valent nickel. Zero-valent nickel then participates in the reaction and becomes divalent nickel again, requiring further reduction by the metal reducing agent.

[0037] As a preferred embodiment, the amount of the metal reducing agent is 1 to 3 times the molar amount of the halobenzoic acid compound. If the amount of reducing agent is too small to establish a catalytic cycle and prevent further reaction, adding 1 to 3 times the molar amount of the substrate is usually most effective.

[0038] As a preferred embodiment, the reductive coupling reaction uses at least one solvent selected from petroleum ether, dichloromethane, trichloromethane, carbon tetrachloride, toluene, benzene, ethyl acetate, methanol, acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, n-pentane, n-hexane, and cyclohexane. The most preferred and effective solvents include N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.

[0039] As a preferred embodiment, the base comprises organic and / or inorganic bases. Inorganic bases include, for example, carbonates, metal hydroxides, metal hydrides, etc., specifically potassium carbonate, sodium carbonate, sodium cyanide, etc.; organic bases include, for example, alkoxides, amines, etc., specifically MeOK, t-BuOK, triethylamine, etc. The amount of base used is preferably 1 to 2 times the molar amount of the halobenzoic acid compound.

[0040] As a preferred embodiment, the reductive coupling reaction is carried out at a temperature of 20–100°C for 1–10 hours. A further preferred reaction temperature is 25–60°C. A further preferred reaction time is 2–3 hours.

[0041] In the preparation of the 2,2'-biphenyl dicarboxylic acid compounds of the present invention, after the reductive coupling reaction is completed, the following post-treatment is performed: the reaction solution is extracted with another solvent (e.g., at least one of n-pentane, n-hexane, cyclohexane, petroleum ether, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, dichloromethane, chloroform, toluene, ethyl acetate, acetonitrile, tetrahydrofuran, or 1,4-dioxane), and then the extract is rotary evaporated and vacuum-sealed to obtain a crude product. The crude product is recrystallized to obtain a purified product. Alternatively, the reaction solution is quenched with 2 mol / L hydrochloric acid, and then extracted with a solvent (at least one of n-pentane, n-hexane, cyclohexane, petroleum ether, methanol, ethanol, dichloromethane, chloroform, toluene, acetone, ethyl acetate, acetonitrile, or tetrahydrofuran), and then separated using rapid column chromatography or plate spectroscopy.

[0042] The method for synthesizing 2,2'-biphenyl dicarboxylic acid compounds according to the present invention can be carried out by reacting in the following ways:

[0043] 1. Weigh and add halobenzoic acid compounds, metal reducing agents and bipyridine ligands to the reaction tube at room temperature. Transfer the reaction tube to a glove box and add base and nickel catalyst to the reaction tube under a nitrogen atmosphere. Finally, add solvent and heat and stir the reaction. Detect the reaction using TLC. After the reaction is complete, use several post-processing steps to purify the product from the reaction solution to obtain a purified product.

[0044] 2. Weigh and add halobenzoic acid compounds, metal reducing agents, and bipyridine ligands to the reaction tube at room temperature. Transfer the reaction tube to a glove box and add alkali and solvent to the reaction tube again under a nitrogen atmosphere. Stir at room temperature for 5 minutes. After the reaction is complete, add Ni metal catalyst again, heat and stir. Detect the reaction using TLC. After the reaction is complete, use several post-processing steps to purify the product from the reaction solution to obtain a purified product.

[0045] 3. Place the reaction tube in a glove box and add nickel catalyst, metal reducing agent and bipyridine ligand to the reaction tube under nitrogen atmosphere. Then add solvent and stir at room temperature for 30 minutes. At this time, the reaction solution is observed to be dark blue. Then add halobenzoic acid compound and base to the solution, and heat and stir the reaction. Detect the reaction using TLC. After the reaction is completed, use several post-processing steps to purify the product from the reaction solution to obtain the purified product.

[0046] 4. Place the reaction tube in a glove box. Under a nitrogen atmosphere, add the nickel catalyst and bipyridine ligand to the reaction tube, then add the solvent and stir at room temperature for 30 minutes. At this time, the reaction solution is observed to be dark blue. Then add the halobenzoic acid compound, metal reducing agent and base to the solution, heat and stir the reaction, and use TLC to detect the reaction. After the reaction is completed, use several post-processing steps to purify the product from the reaction solution to obtain the purified product.

[0047] This invention also proposes a feasible reaction mechanism for the synthesis of 2,2'-biphenyl dicarboxylic acid compounds:

[0048]

[0049] First, the catalyst NiCl2(II)·dme is reduced to Ni(0) by Mn. Then, Ni(0) undergoes ligand exchange with ligand L1. Ni(0)L2 undergoes a first oxidative addition with the template substrate 2-bromobenzoic acid to generate Ni(II)L2, which is then reduced to Ni(I)L2 by metal Mn. Ni(I)L2 undergoes a second oxidative addition with the template substrate to become Ni(III)L2. Ni(III)L2 undergoes direct reductive elimination to obtain the target product and Ni(I)L2. Finally, Ni(I)L2 is reduced to Ni(0)L2 by metal Mn, thus completing the catalytic cycle of the reaction.

[0050] Compared with existing technologies, the beneficial technical effects of the present invention are as follows:

[0051] The method for synthesizing 2,2'-biphenyl dicarboxylic acid compounds of the present invention uses a transition metal nickel catalyst and inexpensive and readily available halobenzoic acid as raw materials, which has the advantage of low cost.

[0052] The method for synthesizing 2,2'-biphenyl dicarboxylic acid compounds of the present invention has strong substrate adaptability. The yield of 2,2'-biphenyl dicarboxylic acid compounds is as high as 80% or more for most substrates, and the yield of 2,2'-biphenyl dicarboxylic acid can reach 93% after scale-up experiments.

[0053] The method for synthesizing 2,2'-biphenyl dicarboxylic acid compounds of the present invention has mild reaction conditions, is achieved through a one-pot process, is simple to operate, highly efficient and rapid, and meets the requirements for industrial production. Detailed Implementation

[0054] The following embodiments are intended to further illustrate the present invention, but not to limit the scope of protection of the claims of the present invention.

[0055] Unless otherwise stated, all reactions were carried out in small reaction tubes.

[0056] All reaction solvents were obtained from commercial sources and used without further purification.

[0057] Product separation was performed using a silica gel column (silica gel particle size 200-300 mesh).

[0058] 1 H NMR (400MHz), 13 C NMR (100MHz) and 19 FNMR (376 MHz) detection was performed using a Bruker ADVANCE III spectrometer. MeOD was used as the solvent, and TMS as the internal standard. Chemical shifts are expressed in parts per million (ppm), with 0.0 ppm of tetramethylsilane as the reference shift. The following abbreviations (or combinations thereof) are used to interpret multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad peak. The coupling constant J is in Hertz (Hz). Chemical shifts are expressed in ppm. 1 1H NMR (400MHz) reference MeOD at the center state of the quintet at 3.31ppm. 13 C NMR (100MHz) references the center line of the seventet at 49.0ppm for MeOD or the center line of the seventet at 39.52ppm for deuterated DMSO.

[0059] I. Screening of reaction conditions:

[0060] Using 2-bromobenzoic acid (0.5 mmol, 1 eq) as a template substrate, the target product 2,2'-biphenyl dicarboxylic acid was synthesized via a nickel-catalyzed reductive coupling reaction, with protonated benzoic acid as a byproduct. Condition screening was conducted for factors such as Ni catalyst type, N ligand type, reducing agent type, base type, solvent type, temperature, and reaction time. Through single-variable screening, the conditions that yielded the highest amount of the target product 2,2'-biphenyl dicarboxylic acid were selected as the optimal reaction conditions. The next step of the reaction was then carried out, and the screening process is shown in the table below:

[0061] Table 1 Screening of conditions for reduction coupling reaction

[0062]

[0063]

[0064]

[0065]

[0066] All yields mentioned above are HPLC yields, with naphthalene as the HPLC internal standard.

[0067] Note: L1: 6,6'-dimethyl-2,2'-dipyridine; L2: 3,4,7,8-tetramethyl-1,10-phenanthroline; L3: 1,10-phenanthroline; L4: 2,9-dimethyl-1,10-phenanthroline; L5: 5,5'-dimethyl-2,2'-dipyridyl; L6: 2,2-bis(2-oxazoline).

[0068] After optimizing the above reaction conditions, the optimal reaction conditions and reaction feed procedure were finally selected as follows: 2-bromobenzoic acid and its derivative (0.5 mmol, 1 eq), Mn as a metal reducing agent (0.75 mmol, 1.5 eq), and L1 ligand (0.08 mmol, 0.16 eq) were weighed and added to the reaction tube at room temperature. The reaction tube was then transferred to a glove box, and under a nitrogen atmosphere, t-BuOK (0.55 mmol, 0.55 eq) and NiCl2·dme (0.04 mmol, 0.08 eq) were added again, followed by DMF (1.5 mL). The mixture was stirred at 40 °C for 2 h, and the reaction was monitored by TLC. After the reaction was complete, the product was purified from the reaction solution using several post-processing steps to obtain a refined product.

[0069] 1. Ligand Selection: The table clearly shows that 6,6'-dimethyl-2,2'-bipyridine, 2,9-dimethyl-1,10-phenanthroline, and oxazoline ligands have high yields. Their structural characteristic is the presence of a methyl group ortho-to the N atom of the bipyridine. It is speculated that the methyl group provides steric hindrance to the reaction after coordination to the Ni catalyst, greatly promoting the coupling reaction. However, when the methyl group is in other positions, this interaction is absent, resulting in a significantly lower yield, almost entirely converting to the protonated byproduct benzoic acid. The 1,10-phenanthroline ligand may not have this effect, and the distance between the two coordinating N atoms is closer than that of the bipyridine ligand, thus the reaction effect is not optimal. Therefore, 6,6'-dimethyl-2,2'-bipyridine is the preferred ligand for this reaction. Without the addition of the ligand, the target product cannot be formed in the reaction system.

[0070] 2. Selection of transition metal Ni catalyst: The table shows that the yields of NiBr2·dme, NiCl2·dppf, and Ni(cod)2 tend to be stable, all above 70%. However, the yield of NiCl2·dme differs by about ten percent, presumably due to differences in the abilities of the original ligands and halogen leaving groups in the Ni catalyst. Ultimately, NiCl2·dme, with the highest yield, was chosen as the catalyst. Without the addition of the transition metal Ni catalyst, the target product 2,2'-biphenyl dicarboxylic acid cannot be formed in the reaction system.

[0071] 3. Selection of Base and its Equivalent: 2,2'-Biphenyldicarboxylic acid is synthesized via a reductive coupling reaction catalyzed by transition metal Ni. Without the addition of a base, self-coupling does not occur. However, the addition of different bases leads to the formation of the target product, 2,2'-biphenyldicarboxylic acid. It is hypothesized that with the addition of a base, the base initially reacts with the carboxylic acid, generating a carboxylate anion. This carboxylate anion coordinates with the empty d-orbitals of the Ni catalyst, narrowing the distance between Ni and the halogen, thus facilitating the first-step oxidative addition. In other words, the addition of the base controls the regioselectivity of the reaction, preventing ortho-coupling and para-coupling. The strength and equivalent amount of the added base significantly affect the system. With the addition of a weak base, K₂CO₃, the yield is only 12%, with most of the reactants remaining unreacted. This may be because the weak base cannot promptly convert the carboxylic acid into a more coordinating carboxylate anion, thus preventing coordination with the Ni catalyst. By increasing the basicity of the added base, such as KH, MeOK, and t-BuOK, the yield exceeded 70%. We ultimately selected t-BuOK, which yielded the highest amount, as the added base for this reaction. Further investigation of the appropriate amount of t-BuOK revealed that adding 2 eq resulted in no formation of the target product. This was likely due to excess t-BuOK coordinating onto the transition metal Ni catalyst, preventing further coordination and thus deactivating the Ni catalyst. Through screening, we ultimately determined that 1.1 eq of t-BuOK yielded the highest yield.

[0072] 4. Screening of Reducing Agents and Their Equivalent Amounts: Both Zn and In reducing agents can generate the coupling product 2,2'-biphenyl dicarboxylic acid, with relatively stable yields above 70%. However, the yield reaches its highest when Mn is used as the reducing agent, possibly due to Mn's wider reduction potential. Therefore, Mn was ultimately selected as the final reducing agent. Further analysis revealed a rapid decrease in yield when the Mn equivalent was reduced. This is because the reducing agent concentration in the system was insufficient to reduce the Ni catalyst to zero valence Ni, preventing the establishment of the final catalytic cycle and thus halting the reaction. Finally, a final Mn equivalent of 1.5 eq was selected as the optimal amount added. Without the addition of a reducing agent, the target product 2,2'-biphenyl dicarboxylic acid could not be generated in the reaction system.

[0073] 5. Solvent Selection and Amount Selection: The table clearly shows that the solvent has a significant impact on this reaction. The reaction can occur with low-polarity ether solvents (such as THF and Dioxane), but the yield is low. The reaction proceeds normally with solvents that are aprotic and highly polar (such as DMF). Therefore, DMF was ultimately selected as the reaction solvent. Reducing the amount of DMF added, adding 0.5 mL and 1.0 mL did not result in a higher yield than adding 1.5 mL. Therefore, 1.5 mL of DMF was ultimately the preferred amount.

[0074] 6. Screening of Reaction Temperature: The reaction is quite sensitive to temperature. If the temperature is too low, the activation energy for the second oxidative addition of 2-bromobenzoic acid with the transition metal Ni(I) catalyst cannot be reached, and the reaction cannot proceed due to the failure to reach the activation energy barrier. If the reaction temperature is too high, the rate of protonation after the first oxidative addition is accelerated, resulting in an increased proportion of the byproduct benzoic acid, thus preventing the acquisition of the target product 2,2'-biphenyldicarboxylic acid.

[0075] 7. Screening of reaction time: Through a series of screenings of reaction time, it was found that the highest yield was achieved when the reaction time was 2 hours. Reactions with a reaction time of less than two hours resulted in incomplete conversion of the reactants, while reactions with a reaction time exceeding two hours or even longer resulted in a slight decrease in yield.

[0076] 8. Screening of the ratio and equivalent amount of transition metal Ni catalyst to ligand: For most transition metal-catalyzed reactions, ligands play a crucial role, and the amount of ligand added needs strict control. Different catalysts interact differently with different ligands; some catalysts have a 1:1 coordination ratio with ligands, while others have a 1:2 ratio. These different ratios create different chemical environments around the transition metal catalyst, leading to varying chemical reactions depending on the amount of ligand added. Therefore, screening the ratio of transition metal Ni catalyst to ligand is very important. For this reaction, the yield of the target product is highest when the catalyst-to-ligand ratio is 1:2, with 8% transition metal Ni catalyst and 16% L1 ligand. Therefore, the optimal ratio of transition metal Ni catalyst to ligand is 1:2, with 8% transition metal Ni catalyst and 16% ligand.

[0077] II. Investigation of the universality of reaction substrates

[0078] Through the above screening, the optimal reaction conditions for the reductive coupling reaction can be obtained. Next, the effect of different substrates on the reaction under the optimal reaction conditions is investigated. Experiments show that the electronegativity of the benzene ring, and the attachment of electron-withdrawing and electron-donating groups to the benzene ring, such as methyl, methoxy, trifluoromethyl, and fluorine atoms, all result in relatively good yields. However, the yield of electron-withdrawing groups is slightly lower than that of electron-donating groups. Secondly, the effect of different leaving groups on the reaction yield is examined. Overall, the reaction yields for iodine and bromine are generally greater than those for chlorine, proving that iodine and bromine are excellent leaving groups. Finally, the universality of functional groups is further studied. The coupling reaction yields are generally good when the structure contains some functional groups, but the reaction yields decrease for some functional groups, such as methyl ketones, cyano groups, and sulfone groups.

[0079] The following are specific examples:

[0080] Example 1

[0081]

[0082] Weigh and add 2-bromobenzoic acid (0.5 mmol, 1 eq, 100 mg), Mn (0.75 mmol, 1.5 eq, 42 mg), and 6,6'-dimethyl-2,2-bipyridine (0.08 mmol, 0.16 eq, 14.8 mg) to the reaction tube at room temperature. Then, transfer the reaction tube to a glove box and, under a nitrogen atmosphere, add t-BuOK (0.55 mmol, 0.55 eq, 62 mg) and NiCl2·dme (0.04 mmol, 0.08 eq, 8.7 mg), followed by 1.5 mL of DMF solvent. Stir at 40 °C for 2 h and monitor the reaction by TLC. After the reaction is complete, ethyl acetate (2 mL) and 2 mol / L HCl (2 mL) are added to quench the reaction. Subsequently, ethyl acetate (20 ml) and water (20 ml) were added for extraction. After standing and separating the layers, the aqueous phase was discarded, and fresh water (20 ml) was added again for extraction. The extraction process was repeated three times, and the organic phase was collected. The solvent was evaporated using a rotary evaporator, and finally, the target product was obtained by polar column chromatography using PE:EA:HCOOH (1:1:0.03) with a yield of 95%.

[0083] 1 H NMR (400MHz, Methanol-d4) δ7.99-7.97(m,2H),7.55-7.51(m,2H),7.44-7.39(m,2H),7.18-7.16(m,2H)ppm. 13C NMR (101MHz, Methanol-d4) δ170.5,145.1,132.4,131.5,131.3,131.0,128.0ppm.

[0084] Example 2

[0085]

[0086] The experimental conditions and procedures were as described in Example 1: using 2-bromo-4-methylbenzoic acid as a substrate, the yield of the target product was 90%.

[0087] 1 H NMR (400MHz, Methanol-d4) δ7.87 (d, J = 8.0 Hz, 2H), 7.23-7.21 (m, 2H), 6.97 (d, J = 1.8 Hz, 2H), 2.39 (s, 6H) ppm. 13 C NMR (101MHz, Methanol-d4) δ170.6,145.4,143.1,132.1,131.2,128.5,128.4,21.4ppm.

[0088] Example 3

[0089]

[0090] The experimental conditions and procedures were as described in Example 1: using 2-bromo-4-methoxybenzoic acid as a substrate, the yield of the target product was 92%.

[0091] 1 H NMR (400MHz, Methanol-d4) δ7.98 (d, J = 8.7Hz, 2H), 6.96-6.93 (m, 2H), 6.67 (d, J = 2.6Hz, 2H), 3.83 (s, 6H) ppm. 13 C NMR (101MHz, Methanol-d4) δ163.4,147.6,133.4,123.3,116.7,113.1,56.0ppm.

[0092] Example 4

[0093]

[0094] The experimental conditions and procedures were as described in Example 1: using 2-bromo-5-fluorobenzoic acid as a substrate, the yield of the target product was 85%.

[0095] 1H NMR (400MHz, Methanol-d4) δ7.70-7.67(m,2H),7.32-7.27(m,2H),7.20-7.17(m,2H)ppm. 13 C NMR (101MHz, Methanol-d4) δ 168.8, 164.2, 161.7, 140.2 (d, J = 3.6Hz), 133.5 (d, J = 7.6Hz), 133.3 (d, J = 7.2Hz), 119.2 (d, J = 21.5Hz), 117.6 (d, J = 23.6Hz) ppm. 19 F NMR (376MHz, Methanol-d4) δ-117.36ppm.

[0096] Example 5

[0097]

[0098] The experimental conditions and procedures were as described in Example 1: using 2-bromo-4,5-difluorobenzoic acid as a substrate, the yield of the target product was 80%.

[0099] 1 H NMR (400MHz, Methanol-d4) δ7.93-7.88(m,2H),7.17-7.12(m,2H)ppm. 13 C NMR(101MHz, Methanol-d4)δ167.5,154.3(d,J=12.8Hz),151.8(d,J=12.9Hz),151.5(d,J=12.7Hz),149.0( d, J=12.8Hz), 141.1, 141.0 (d, J=4.5Hz), 128.2, 120.6 (d, J=1.6Hz), 120.5, 120.4 (d, J=1.5Hz), 120.3ppm. 19 F NMR (376MHz, Methanol-d4) δ -135.41 (d, J = 21.0Hz), -141.50 (d, J = 21.1Hz) ppm.

[0100] Example 6

[0101]

[0102] The experimental conditions and procedures were as described in Example 1: using 2-bromo-6-(trifluoromethoxy)benzoic acid as a substrate, the yield of the target product was 81%.

[0103] 1H NMR (400MHz, Methanol-d4) δ7.58-7.54(m,2H),7.45-7.42(m,2H),7.35-7.33(m,2H)ppm. 13 C NMR (101MHz, Methanol-d4) δ 168.1, 147.0 (d, J = 2.0Hz), 140.5, 131.5, 129.9, 129.8, 125.7, 123.2, 121.6 (d, J = 1.5Hz), 120.6, 118.1ppm. 19 F NMR (377MHz, Methanol-d4) δ-58.74ppm.

[0104] Example 7

[0105]

[0106] The experimental conditions and procedures were as described in Example 1: using 2-iodo-4,5-dimethoxybenzoic acid as a substrate, the yield of the target product was 96%.

[0107] 1 H NMR (400MHz, DMSO-d6) δ7.40(s,2H),6.66(s,2H),3.81(s,6H),3.76(s,6H)ppm. 13 C NMR (101MHz, DMSO-d6) δ167.6,150.6,146.9,137.4,122.4,113.8,112.7,55.7,55.7ppm.

[0108] Example 8

[0109]

[0110] Under a nitrogen atmosphere, 2-bromo-5-hydroxybenzaldehyde (7.462 mmol, 1 eq, 1.5 g), potassium carbonate (11.2 mmol, 1.5 eq, 1.55 g), and DMF solvent (20 mL) were added to the reaction flask. Finally, bromomethylcyclopropane (7.462 mmol, 1 eq, 1 g) was slowly added. After reacting at room temperature for 2-3 h, ethyl acetate (20 mL) and water (20 mL) were added for extraction. After standing and separating the layers, the aqueous phase was discarded, and fresh water (20 mL x 2) was added for extraction again. This extraction process was repeated three times, and the organic phase was collected. The solvent was evaporated to dryness using a rotary evaporator, and finally, the target product was obtained by polar column chromatography using PE:EA (100:1) with a yield of 87%.

[0111] Under a nitrogen atmosphere, 2-bromo-5-(cyclopropylmethoxy)benzaldehyde (5 mmol, 1 eq, 1 g), sodium chlorite (10 mmol, 2 eq, 0.9 g), 2-methyl-2-butene (50 mmol, 10 eq, 3.5 g), tert-butanol (10 mL), and THF (10 mL) were added to the reaction flask. Sodium dihydrogen phosphate (35 mmol, 7 eq, 4.2 g) was slowly added. After stirring at room temperature for 2-3 h, ethyl acetate (20 mL) and water (20 mL) were added for extraction. After standing and separating the layers, the aqueous phase was discarded, and the organic phase was collected. The solvent was evaporated using a rotary evaporator, and the target product was obtained by polar column chromatography using PE:EA (1:1) with a yield of 80%.

[0112] The experimental conditions and procedures were as described in Example 1: using the prepared 2-bromo-5-(cyclopropylmethoxy)benzoic acid as the substrate, the yield of the target product was 84%.

[0113] 1 H NMR (400MHz, Methanol-d4) δ7.45(d,J=1.8Hz,2H),7.06(s,4H),3.88(d,J=6.9Hz,4H),1.34-1.24(m,2H),0.66-0.61(m,4H),0.38(d,J=5.0Hz,4H)ppm. 13 C NMR (101MHz, Methanol-d4) δ170.6,159.2,136.8,133.0,132.6,118.7,116.6,74.0,11.2,3.6ppm.

[0114] Example 9

[0115]

[0116] Under a nitrogen atmosphere, 2-bromo-5-hydroxybenzaldehyde (7.462 mmol, 1 eq, 1.5 g), potassium carbonate (11.2 mmol, 1.5 eq, 1.55 g), and DMF solvent (20 mL) were added to the reaction flask. Finally, bromomethylcyclobutane (7.462 mmol, 1 eq, 1.11 g) was slowly added. After reacting at room temperature for 2-3 h, ethyl acetate (20 mL) and water (20 mL) were added for extraction. After standing and separating the layers, the aqueous phase was discarded, and fresh water (20 mL x 2) was added for extraction again. This extraction process was repeated three times, and the organic phase was collected. The solvent was evaporated to dryness using a rotary evaporator, and finally, the target product was obtained by polar column chromatography using PE:EA (100:1) with a yield of 90%.

[0117] Under a nitrogen atmosphere, 2-bromo-5-(cyclobutylmethoxy)benzaldehyde (5 mmol, 1 eq, 1.34 g), sodium chlorite (10 mmol, 2 eq, 0.9 g), 2-methyl-2-butene (50 mmol, 10 eq, 3.5 g), tert-butanol (10 mL), and THF (10 mL) were added to the reaction flask. Sodium dihydrogen phosphate (35 mmol, 7 eq, 4.2 g) was slowly added. After stirring at room temperature for 2-3 h, ethyl acetate (20 mL) and water (20 mL) were added for extraction. After standing and separating the layers, the aqueous phase was discarded, and the organic phase was collected. The solvent was evaporated using a rotary evaporator, and the target product was obtained by polar column chromatography using PE:EA (1:1) with a yield of 83%.

[0118] The experimental conditions and procedures were as described in Example 1: using the prepared 2-bromo-5-(cyclobutylmethoxy)benzaldehyde as a substrate, the yield of the target product was 82%.

[0119] 1 H NMR (400MHz, Methanol-d4) δ7.46(s,2H),7.06(s,4H),4.00(d,J=6.5Hz,4H),2.86-2.75(m,2H),2.19-2.13(m,4H),2.07-1.89(m,8H)ppm. 13 C NMR (101MHz, Methanol-d4) δ170.6,159.4,136.7,133.0,132.6,118.6,116.5,73.4,36.1,25.8,19.4ppm.

[0120] Example 10

[0121]

[0122] The experimental conditions and procedures were as described in Example 1: using 5-chloro-2-iodobenzoic acid as a substrate, the yield of the target product was 75%.

[0123] 1 H NMR (400MHz, Methanol-d4) δ7.97 (d, J = 2.3Hz, 2H), 7.56-7.53 (m, 2H), 7.17-7.14 (m, 2H) ppm. 13 C NMR (101MHz, Methanol-d4) δ168.5,142.6,134.2,133.0,132.9,132.4,130.9ppm.

[0124] Example 11

[0125]

[0126] The experimental conditions and procedures were as described in Example 1: using 2-bromo-4-trifluoromethylbenzoic acid as a substrate, the yield of the target product was 72%.

[0127] 1 H NMR (400MHz, Methanol-d4) δ8.20 (d, J = 8.2Hz, 2H), 7.80-7.78 (m, 2H), 7.50 (d, J = 1.8Hz, 2H) ppm. 13 C NMR(101MHz,Methanol-d4)δ168.6,144.4,134.9,134.5,134.2,133.9,133.5, 132.0, 129.2, 128.0 (q, J = 3.9Hz), 126.5, 125.5 (q, J = 3.8Hz), 123.8, 121.1ppm. 19 F NMR (377MHz, Methanol-d4) δ-64.45ppm.

[0128] Example 12

[0129]

[0130] The experimental conditions and procedures were as described in Example 1: using 2-iodobenzoic acid as a substrate, the yield of the target product was 96%.

[0131] 1 H NMR (400MHz, Methanol-d4) δ7.99-7.97(m,2H),7.55-7.51(m,2H),7.44-7.39(m,2H),7.18-7.16(m,2H)ppm. 13 C NMR (101MHz, Methanol-d4) δ170.5,145.0,132.4,131.5,131.3,131.0,128.0ppm.

[0132] Example 13

[0133]

[0134] The experimental conditions and procedures were as described in Example 1: using 2-iodo-5-fluorobenzoic acid as a substrate, the yield of the target product was 83%.

[0135] 1 H NMR (400MHz, Methanol-d4) δ7.70-7.67(m,2H),7.32-7.27(m,2H),7.21-7.17(m,2H)ppm.13 C NMR (101MHz, Methanol-d4) δ 168.8, 164.2, 161.8, 140.2 (d, J = 3.5Hz), 133.5 (d, J = 7.6Hz), 133.4 (d, J = 7.1Hz), 119.2 (d, J = 21.4Hz), 117.6 (d, J = 23.5Hz) ppm. 19 F NMR (377MHz, Methanol-d4) δ-117.36ppm.

[0136] Example 14

[0137]

[0138] The experimental conditions and procedures were as described in Example 1: using 2-chlorobenzoic acid as a substrate, the yield of the target product was 80%.

[0139] 1 H NMR (400MHz, Methanol-d4) δ7.99-7.97(m,2H),7.55-7.50(m,2H),7.41(t,J=7.6Hz,2H),7.17(d,J=7.6Hz,2H)ppm. 13 C NMR (101MHz, Methanol-d4) δ170.6,145.0,132.4,131.5,131.3,131.0,128.0ppm.

[0140] Example 15

[0141]

[0142] The experimental conditions and procedures were as described in Example 1: using 2-chloro-5-methoxybenzoic acid as a substrate, the yield of the target product was 71%.

[0143] 1 H NMR (400MHz, Methanol-d4) δ7.47 (t, J = 1.6 Hz, 2H), 7.08 (d, J = 1.5 Hz, 4H), 3.86 (s, 6H) ppm. 13 C NMR (101MHz, Methanol-d4) δ170.6,159.8,136.7,133.1,132.8,118.0,115.9,55.9ppm.

[0144] Example 16

[0145]

[0146] The experimental conditions and procedures were as described in Example 1: using 2-chloro-5-methylbenzoic acid as a substrate, the yield of the target product was 75%.

[0147] 1 H NMR (400MHz, Methanol-d4) δ7.77 (d, J = 1.9 Hz, 2H), 7.33-7.30 (m, 2H), 7.03 (d, J = 7.8 Hz, 2H), 2.40 (s, 6H) ppm. 13 C NMR (101MHz, Methanol-d4) δ170.9,142.0,137.8,132.9,131.6,131.4,131.3,21.0ppm.

[0148] Example 17

[0149]

[0150] The experimental conditions and procedures were as described in Example 1: using 4-acetyl-2-chlorobenzoic acid as a substrate, the yield of the target product was 59%.

[0151] 1 H NMR (400MHz, Methanol-d4) δ8.06 (d, J = 8.0 Hz, 2H), 7.95 (d, J = 8.0 Hz, 2H), 7.77 (s, 2H), 2.62 (s, 6H) ppm. 13 C NMR (101MHz, Methanol-d4) δ199.6,142.5,139.5,130.9,130.5,129.2,128.6,26.9ppm.

[0152] Example 18

[0153]

[0154] The experimental conditions and procedures were as described in Example 1: using 2-chloro-4-methylsulfonylbenzoic acid as a substrate, the yield of the target product was 54%.

[0155] 1 H NMR (400MHz, Methanol-d4) δ8.25 (d, J = 8.2 Hz, 2H), 8.08-8.06 (m, 2H), 7.83 (d, J = 1.9 Hz, 2H), 3.19 (s, 6H) ppm. 13 C NMR (101MHz, Methanol-d4) δ168.4,144.4,144.3,136.2,132.3,130.0,127.7,44.1ppm.

[0156] Example 19

[0157]

[0158] Under a nitrogen atmosphere, 2-bromo-5-hydroxybenzaldehyde (7.462 mmol, 1 eq, 1.5 g), potassium carbonate (11.2 mmol, 1.5 eq, 1.55 g), and DMF solvent (20 mL) were added to the reaction flask. Finally, bromomethylcyclohexane (7.462 mmol, 1 eq, 1.32 g) was slowly added. After reacting at room temperature for 2-3 h, ethyl acetate (20 mL) and water (20 mL) were added for extraction. After standing and separating the layers, the aqueous phase was discarded, and fresh water (20 mL x 2) was added for extraction again. This extraction process was repeated three times, and the organic phase was collected. The solvent was evaporated to dryness using a rotary evaporator, and finally, the target product was obtained by polar column chromatography using PE:EA (100:1) with a yield of 93%.

[0159] Under a nitrogen atmosphere, 2-bromo-5-(cyclohexylmethoxy)benzaldehyde (5 mmol, 1 eq, 1.48 g), sodium chlorite (10 mmol, 2 eq, 0.9 g), 2-methyl-2-butene (50 mmol, 10 eq, 3.5 g), tert-butanol (10 mL), and THF (10 mL) were added to the reaction flask. Sodium dihydrogen phosphate (35 mmol, 7 eq, 4.2 g) was slowly added. After stirring at room temperature for 2-3 h, ethyl acetate (20 mL) and water (20 mL) were added for extraction. After standing and separating the layers, the aqueous phase was discarded, and the organic phase was collected. The solvent was evaporated using a rotary evaporator, and the target product was obtained by polar column chromatography using PE:EA (1:1) with a yield of 75%.

[0160] The experimental conditions and procedures were as described in Example 1: using the prepared 2-bromo-5-(cyclohexylmethoxy)benzoic acid as a substrate, the yield of the target product was 79%.

[0161] 1 H NMR(400MHz,Methanol-d4)δ7.44(t,J=1.5Hz,2H),7.06(d,J=1.6Hz,4H),3.83 (d,J=6.3Hz,4H),1.93-1.71(m,12H),1.41-1.23(m,6H),1.18-1.08(m,4H)ppm. 13 CNMR(101MHz,Methanol-d4)δ170.6,159.4,136.7,133.0,132.6,118.6,116.5,74.8,39.1,30.9,27.7,27.0ppm.

[0162] Example 20

[0163]

[0164] Under a nitrogen atmosphere, 2-bromo-5-hydroxybenzaldehyde (7.462 mmol, 1 eq, 1.5 g), potassium carbonate (11.2 mmol, 1.55 g, 1.55 g), and DMF solvent (20 mL) were added to the reaction flask. Finally, 5-bromo-2-methylpent-2-ene (7.462 mmol, 1 eq, 1.22 g) was slowly added. After reacting at room temperature for 2-3 h, ethyl acetate (20 mL) and water (20 mL) were added for extraction. After standing and separating the layers, the aqueous phase was discarded, and fresh water (20 mL x 2) was added for extraction again. This extraction process was repeated three times, and the organic phase was collected. The solvent was evaporated to dryness using a rotary evaporator, and finally, the target product was obtained by polar column chromatography using PE:EA (100:1) with a yield of 96%.

[0165] Under a nitrogen atmosphere, 2-bromo-5-((4-methylpent-3-en-1-yl)oxy)benzaldehyde (5 mmol, 1 eq, 1.41 g), sodium chlorite (10 mmol, 2 eq, 0.9 g), 2-methyl-2-butene (50 mmol, 10 eq, 3.5 g), tert-butanol (10 mL), and THF (10 mL) were added to a reaction flask. Sodium dihydrogen phosphate (35 mmol, 7 eq, 4.2 g) was slowly added. After stirring at room temperature for 2-3 h, ethyl acetate (20 mL) and water (20 mL) were added for extraction. After standing and separating the layers, the aqueous phase was discarded, and the organic phase was collected. The solvent was evaporated using a rotary evaporator, and the target product was obtained by polar column chromatography using PE:EA (1:1) with a yield of 85%.

[0166] The experimental conditions and procedures were as described in Example 1: using 2-bromo-5-((4-methylpent-3-en-1-yl)oxy)benzoic acid as the substrate, the target product was obtained in 80% yield.

[0167] 1 H NMR (400MHz, Methanol-d4) δ7.46(s,2H),7.06(s,4H),5.26(t,J=7.3Hz,2H),4.00(t,J=6.8Hz,4H),2.49(q,J=7.0Hz,4H),1.74(s,6H),1.69(s,6H)ppm. 13 C NMR (101MHz, Methanol-d4) δ170.5,159.1,136.8,135.2,133.0,132.6,121.0,118.6,116.6,69.1,29.2,25.9,17.9ppm.

[0168] Example 21

[0169]

[0170] Under a nitrogen atmosphere, 2-bromo-5-hydroxybenzaldehyde (7.462 mmol, 1 eq, 1.5 g), potassium carbonate (11.2 mmol, 1.5 eq, 1.55 g), and DMF solvent (20 mL) were added to the reaction flask. Finally, tert-butyldimethylchlorosilane (7.462 mmol, 1 eq, 1.13 g) was slowly added. After reacting at room temperature for 2-3 h, ethyl acetate (20 mL) and water (20 mL) were added for extraction. After standing and separating the layers, the aqueous phase was discarded, and fresh water (20 mL x 2) was added for extraction again. This extraction process was repeated three times, and the organic phase was collected. The solvent was evaporated to dryness using a rotary evaporator, and finally, the target product was obtained by polar column chromatography using PE:EA (100:1) with a yield of 98%.

[0171] Under a nitrogen atmosphere, 2-bromo-5-((tert-butyldimethylsilyl)oxy)benzaldehyde (5 mmol, 1 eq, 1.57 g), sodium chlorite (10 mmol, 2 eq, 0.9 g), 2-methyl-2-butene (50 mmol, 10 eq, 3.5 g), tert-butanol (10 mL), and THF (10 mL) were added to the reaction flask. Sodium dihydrogen phosphate (35 mmol, 7 eq, 4.2 g) was slowly added. After stirring at room temperature for 2-3 h, ethyl acetate (20 mL) and water (20 mL) were added for extraction. After standing and separating the layers, the aqueous phase was discarded, and the organic phase was collected. The solvent was evaporated using a rotary evaporator, and the target product was obtained by polar column chromatography using PE:EA (1:1) with a yield of 87%.

[0172] The experimental conditions and procedures were as described in Example 1: using 2-bromo-5-((tert-butyldimethylsilyl)oxy)benzoic acid as the substrate, the yield of the target product was 58%.

[0173] 1 H NMR (400MHz, Methanol-d4) δ7.15 (d, J = 2.6Hz, 2H), 7.01 (d, J = 8.3Hz, 2H), 6.90-6.88 (m, 2H), 1.02 (s, 18H), 0.25 (s, 12H) ppm. 13 C NMR (101 MHz, Methanol-d4) δ 156.0, 137.6, 134.8, 132.7, 130.3, 122.3, 120.5, 26.1, 19.1, -4.3 ppm. Example 22

[0174]

[0175] Under a nitrogen atmosphere, 2-bromo-5-hydroxybenzaldehyde (7.462 mmol, 1 eq, 1.5 g), potassium carbonate (11.2 mmol, 1.5 eq, 1.55 g), and DMF solvent (20 mL) were added to the reaction flask. Finally, triisopropylchlorosilane (7.462 mmol, 1 eq, 1.44 g) was slowly added. After reacting at room temperature for 2-3 h, ethyl acetate (20 mL) and water (20 mL) were added for extraction. After standing and separating the layers, the aqueous phase was discarded, and fresh water (20 mL x 2) was added for extraction again. This extraction process was repeated three times, and the organic phase was collected. The solvent was evaporated to dryness using a rotary evaporator, and finally, the target product was obtained by polar column chromatography using PE:EA (100:1) with a yield of 92%.

[0176] Under a nitrogen atmosphere, 2-bromo-5-((triisopropylsilyl)oxy)benzaldehyde (5 mmol, 1 eq, 1.78 g), sodium chlorite (10 mmol, 2 eq, 0.9 g), 2-methyl-2-butene (50 mmol, 10 eq, 3.5 g), tert-butanol (10 mL), and THF (10 mL) were added to the reaction flask. Sodium dihydrogen phosphate (35 mmol, 7 eq, 4.2 g) was slowly added. After stirring at room temperature for 2-3 h, ethyl acetate (20 mL) and water (20 mL) were added for extraction. After standing and separating the layers, the aqueous phase was discarded, and the organic phase was collected. The solvent was evaporated using a rotary evaporator, and the target product was obtained by polar column chromatography using PE:EA (1:1) with a yield of 74%.

[0177] The experimental conditions and procedures were as described in Example 1: using 2-bromo-5-((triisopropylsilyl)oxy)benzoic acid as the substrate, the target product was obtained in a yield of 60%.

[0178] 1 H NMR (400MHz, Methanol-d4) δ7.47-7.46(m,2H),7.05-7.04(m,4H),1.36-1.27(m,6H),1.16(d,J=7.3Hz,36H)ppm. 13 C NMR (101MHz, Methanol-d4) δ170.4,156.1,137.6,133.1,132.6,123.7,122.0,18.4,13.9ppm.

[0179] Example 23

[0180]

[0181] Under a nitrogen atmosphere, 2-bromo-5-hydroxybenzaldehyde (7.462 mmol, 1 eq, 1.5 g), potassium carbonate (11.2 mmol, 1.5 eq, 1.55 g), and DMF solvent (20 mL) were added to the reaction flask. Finally, 1-bromobutane (7.462 mmol, 1 eq, 1.02 g) was slowly added. After reacting at room temperature for 2-3 h, ethyl acetate (20 mL) and water (20 mL) were added for extraction. After standing and separating the layers, the aqueous phase was discarded, and fresh water (20 mL x 2) was added for extraction again. This extraction process was repeated three times, and the organic phase was collected. The solvent was evaporated to dryness using a rotary evaporator, and finally, the target product was obtained by polar column chromatography using PE:EA (100:1) with a yield of 96%.

[0182] Under a nitrogen atmosphere, 2-bromo-5-(butoxy)benzaldehyde (5 mmol, 1 eq, 1.28 g), sodium chlorite (10 mmol, 2 eq, 0.9 g), 2-methyl-2-butene (50 mmol, 10 eq, 3.5 g), tert-butanol (10 mL), and THF (10 mL) were added to the reaction flask. Sodium dihydrogen phosphate (35 mmol, 7 eq, 4.2 g) was slowly added. After stirring at room temperature for 2-3 h, ethyl acetate (20 mL) and water (20 mL) were added for extraction. After standing and separating the layers, the aqueous phase was discarded, and the organic phase was collected. The solvent was evaporated using a rotary evaporator, and the target product was obtained by polar column chromatography using PE:EA (1:1) with a yield of 84%.

[0183] The experimental conditions and procedures were as described in Example 1: using the prepared 2-bromo-5-(butoxy)benzoic acid as the substrate, the yield of the target product was 83%.

[0184] 1 H NMR(400MHz, Methanol-d4)δ7.45(d,J=1.7Hz,2H),7.06(d,J=1.3Hz,4H),4.04(t, J=6.4Hz,4H),1.83-1.76(m,4H),1.54(q,J=7.5Hz,4H),1.01(t,J=7.4Hz,6H)ppm. 13 C NMR (101MHz, Methanol-d4) δ170.6,159.3,136.7,133.0,132.6,118.5,116.5,69.0,32.5,20.3,14.2ppm.

[0185] Example 24

[0186]

[0187] Under a nitrogen atmosphere, 2-bromo-5-hydroxybenzaldehyde (7.462 mmol, 1 eq, 1.5 g), potassium carbonate (11.2 mmol, 1.5 eq, 1.55 g), and DMF solvent (20 mL) were added to the reaction flask. Finally, 3-bromopropyl methyl ether (7.462 mmol, 1 eq, 1.14 g) was slowly added. After reacting at room temperature for 2-3 h, ethyl acetate (20 mL) and water (20 mL) were added for extraction. After standing and separating the layers, the aqueous phase was discarded, and fresh water (20 mL x 2) was added for extraction again. This extraction process was repeated three times, and the organic phase was collected. The solvent was evaporated to dryness using a rotary evaporator, and finally, the target product was obtained by polar column chromatography using PE:EA (100:1) with a yield of 90%.

[0188] Under a nitrogen atmosphere, 2-bromo-5-(3-methoxypropoxy)benzaldehyde (5 mmol, 1 eq, 1.36 g), sodium chlorite (10 mmol, 2 eq, 0.9 g), 2-methyl-2-butene (50 mmol, 10 eq, 3.5 g), tert-butanol (10 mL), and THF (10 mL) were added to the reaction flask. Sodium dihydrogen phosphate (35 mmol, 7 eq, 4.2 g) was slowly added. After stirring at room temperature for 2-3 h, ethyl acetate (20 mL) and water (20 mL) were added for extraction. After standing and separating the layers, the aqueous phase was discarded, and the organic phase was collected. The solvent was evaporated using a rotary evaporator, and the target product was obtained by polar column chromatography using PE:EA (1:1) with a yield of 81%.

[0189] The experimental conditions and procedures were as described in Example 1: using the prepared 2-bromo-5-(3-methoxypropoxy)benzoic acid as the substrate, the yield of the target product was 80%.

[0190] 1 H NMR (400MHz, Methanol-d4) δ7.47(d,J=1.6Hz,2H),7.07(d,J=1.5Hz,4H),4.12(t,J=6.2Hz,4H),3.59(t,J=6.2Hz,4H),3.36(s,6H),2.08-2.02(m,4H)ppm. 13 C NMR (101MHz, Methanol-d4) δ170.5,159.1,136.8,133.1,132.6,118.5,116.5,70.3,66.2,58.9,30.6ppm.

[0191] Example 25

[0192]

[0193] Under a nitrogen atmosphere, 2-bromo-5-hydroxybenzaldehyde (7.462 mmol, 1 eq, 1.5 g), potassium carbonate (11.2 mmol, 1.5 eq, 1.55 g), and DMF solvent (20 mL) were added to the reaction flask. Finally, 1-bromo-4,4,4-trifluorobutane (7.462 mmol, 1 eq, 1.43 g) was slowly added. After reacting at room temperature for 2-3 h, ethyl acetate (20 mL) and water (20 mL) were added for extraction. After standing and separating the layers, the aqueous phase was discarded, and fresh water (20 mL x 2) was added for extraction again. This extraction process was repeated three times, and the organic phase was collected. The solvent was evaporated to dryness using a rotary evaporator, and the target product was obtained by polar column chromatography using PE:EA (100:1) in 85% yield.

[0194] Under a nitrogen atmosphere, 2-bromo-5-(4,4,4-trifluorobutoxy)benzaldehyde (5 mmol, 1 eq, 1.55 g), sodium chlorite (10 mmol, 2 eq, 0.9 g), 2-methyl-2-butene (50 mmol, 10 eq, 3.5 g), tert-butanol (10 mL), and THF (10 mL) were added to the reaction flask. Sodium dihydrogen phosphate (35 mmol, 7 eq, 4.2 g) was slowly added. After stirring at room temperature for 2-3 h, ethyl acetate (20 mL) and water (20 mL) were added for extraction. After standing and separating the layers, the aqueous phase was discarded, and the organic phase was collected. The solvent was evaporated using a rotary evaporator, and the target product was obtained by polar column chromatography using PE:EA (1:1) with a yield of 73%.

[0195] The experimental conditions and procedures were as described in Example 1: using the prepared 2-bromo-5-(4,4,4-trifluorobutoxy)benzoic acid as the substrate, the yield of the target product was 79%.

[0196] 1 H NMR (400MHz, Methanol-d4) δ7.40 (s, 2H), 7.06 (s, 4H), 4.11 (t, J = 6.1Hz, 4H), 2.45-2.33 (m, 4H), 2.09-2.02 (m, 4H) ppm. 13 C NMR (101MHz, Methanol-d4) δ 171.8, 159.0, 136.1, 134.2, 133.0, 130.2, 127.5, 124.7, 118.1, 116.0, 31.4 (q, J = 29.0Hz), 23.3 (d, J = 3.1Hz) ppm. 19 F NMR (376MHz, Methanol-d4) δ -67.94ppm. Example 26

[0197]

[0198] Under a nitrogen atmosphere, 2-bromo-5-hydroxybenzaldehyde (7.462 mmol, 1 eq, 1.5 g), potassium carbonate (11.2 mmol, 1.5 eq, 1.55 g), and DMF solvent (20 mL) were added to the reaction flask. Finally, 4-bromobutyronitrile (7.462 mmol, 1 eq, 1.03 g) was slowly added. After reacting at room temperature for 2-3 h, ethyl acetate (20 mL) and water (20 mL) were added for extraction. After standing and separating the layers, the aqueous phase was discarded, and fresh water (20 mL x 2) was added for extraction again. This extraction process was repeated three times, and the organic phase was collected. The solvent was evaporated to dryness using a rotary evaporator, and finally, the target product was obtained by polar column chromatography using PE:EA (100:1) with a yield of 91%.

[0199] Under a nitrogen atmosphere, 2-bromo-5-(3-cyanopropoxy)benzaldehyde (5 mmol, 1 eq, 1.34 g), sodium chlorite (10 mmol, 2 eq, 0.9 g), 2-methyl-2-butene (50 mmol, 10 eq, 3.5 g), tert-butanol (10 mL), and THF (10 mL) were added to the reaction flask. Sodium dihydrogen phosphate (35 mmol, 7 eq, 4.2 g) was slowly added. After stirring at room temperature for 2-3 h, ethyl acetate (20 mL) and water (20 mL) were added for extraction. After standing and separating the layers, the aqueous phase was discarded, and the organic phase was collected. The solvent was evaporated using a rotary evaporator, and the target product was obtained by polar column chromatography using PE:EA (1:1) with a yield of 79%.

[0200] The experimental conditions and procedures were as described in Example 1: using the prepared 2-bromo-5-(3-cyanopropoxy)benzoic acid as the substrate, the yield of the target product was 60%.

[0201] 1 H NMR (400MHz, Methanol-d4) δ7.48(d,J=2.3Hz,2H),7.10(d,J=3.5Hz,4H),4.16(t,J=5.8Hz,4H),2.69(t,J=7.1Hz,4H),2.19-2.12(m,4H)ppm. 13 C NMR (101MHz, Methanol-d4) δ170.6,158.8,136.9,133.1,133.0,120.8,118.5,116.5,67.2,26.4,14.5ppm.

[0202] Example 27

[0203]

[0204] Under a nitrogen atmosphere, 5-amino-2-bromobenzoic acid (4.629 mmol, 1 eq, 1 g), triethylamine (6.944 mmol, 1.5 eq, 0.7 g), and THF (15 mL) were added to the reaction flask. Finally, BocCl (5.1 mmol, 1.1 eq, 0.62 g) was slowly added at 0 °C. After stirring at 0 °C for 2–3 h, ethyl acetate (20 mL) and water (20 mL) were added for extraction. After standing and separation, the aqueous phase was discarded, and the organic phase was collected. The solvent was evaporated to dryness using a rotary evaporator. Finally, the target product was obtained by polar column chromatography using PE:EA (1:1), with a yield of 71%.

[0205] The experimental conditions and procedures were as described in Example 1: using the prepared 2-bromo-5-((tert-butoxycarbonyl)amino)benzoic acid as the substrate, the yield of the target product was 86%.

[0206] 1 H NMR (400MHz, Methanol-d4) δ8.00 (d, J = 2.4Hz, 2H), 7.59-7.56 (m, 2H), 7.07 (d, J = 8.3Hz, 2H), 1.54 (s, 18H) ppm. 13 C NMR (101MHz, Methanol-d4) δ170.6,155.2,139.6,138.6,132.2,132.1,122.2,120.9,81.1,28.7ppm.

[0207] Example 28

[0208]

[0209] Under a nitrogen atmosphere, 5-amino-2-bromobenzoic acid (4.629 mmol, 1 eq, 1 g), triethylamine (6.944 mmol, 1.5 eq, 0.7 g), and THF (15 mL) were added to the reaction flask. Cyclopentylformyl chloride (5.1 mmol, 1.1 eq, 0.68 g) was then slowly added at 0 °C. After stirring at 0 °C for 2–3 h, ethyl acetate (20 mL) and water (20 mL) were added for extraction. After standing and separation, the aqueous phase was discarded, and the organic phase was collected. The solvent was evaporated to dryness using a rotary evaporator. Finally, the target product was obtained by polar column chromatography using PE:EA (1:1), with a yield of 70%.

[0210] Weigh and add the prepared 2-bromo-5-(cyclopentanecarboxamide)benzoic acid (0.5 mmol, 1 eq, 156 mg), Mn (0.75 mmol, 1.5 eq, 42 mg), and 6,6'-dimethyl-2,2-bipyridine (0.08 mmol, 0.16 eq, 14.8 mg) to the reaction tube at room temperature. Then, transfer the reaction tube to a glove box and, under a nitrogen atmosphere, add t-BuOK (0.55 mmol, 0.55 eq, 62 mg) and NiCl2·dme (0.04 mmol, 0.08 eq, 8.7 mg), followed by 1.5 mL of DMF solvent. Stir at 40 °C for 2 h and monitor the reaction by TLC. After the reaction is complete, ethyl acetate (2 mL) and 2 mol / L HCl (2 mL) are added to quench the reaction. Subsequently, ethyl acetate (20 ml) and water (20 ml) were added for extraction. After standing and separating the layers, the aqueous phase was discarded, and fresh water (20 ml) was added again for extraction. The extraction process was repeated three times, and the organic phase was collected. The solvent was evaporated using a rotary evaporator, and finally, the target product was obtained by polar column chromatography using PE:EA:HCOOH (1:1:0.03) with a yield of 82%.

[0211] 1 H NMR(400MHz, Methanol-d4)δ8.06(d,J=2.2Hz,2H),7.74-7.72(m,2H),7.08(d,J=8.3H z,2H),2.87-2.79(m,2H),1.99-1.90(m,4H),1.88-1.74(m,8H),1.70-1.60(m,4H)ppm. 13 C NMR (101MHz, Methanol-d4) δ177.9,171.8,139.2,138.7,133.6,131.9,123.1,121.7,47.3,31.6,27.1ppm.

[0212] Example 29

[0213]

[0214] Under a nitrogen atmosphere, 5-amino-2-bromobenzoic acid (4.629 mmol, 1 eq, 1 g), triethylamine (6.944 mmol, 1.5 eq, 0.7 g), and THF (15 mL) were added to the reaction flask. Isobutyryl chloride (5.1 mmol, 1.1 eq, 0.55 g) was then slowly added at 0 °C. After stirring at 0 °C for 2–3 h, ethyl acetate (20 mL) and water (20 mL) were added for extraction. After standing and separation, the aqueous phase was discarded, and the organic phase was collected. The solvent was evaporated to dryness using a rotary evaporator. Finally, the target product was obtained by polar column chromatography using PE:EA (1:1) with a yield of 77%.

[0215] Weigh and add the prepared 2-bromo-5-isopyranobenzoic acid (0.5 mmol, 1 eq, 157 mg), Mn (0.75 mmol, 1.5 eq, 42 mg), and 6,6'-dimethyl-2,2-bipyridine (0.08 mmol, 0.16 eq, 14.8 mg) to the reaction tube at room temperature. Then, transfer the reaction tube to a glove box and, under a nitrogen atmosphere, add t-BuOK (0.55 mmol, 0.55 eq, 62 mg) and NiCl2·dme (0.04 mmol, 0.08 eq, 8.7 mg), and finally add the solvent DMF (1.5 mL). Stir at 40 °C for 2 h, and monitor the reaction using TLC. After the reaction is complete, ethyl acetate (2 mL) and 2 mol / L HCl (2 mL) are added to quench the reaction. Subsequently, ethyl acetate (20 ml) and water (20 ml) were added for extraction. After standing and separating the layers, the aqueous phase was discarded, and fresh water (20 ml) was added again for extraction. The extraction process was repeated three times, and the organic phase was collected. The solvent was evaporated using a rotary evaporator, and finally, the target product was obtained by polar column chromatography using PE:EA:HCOOH (1:1:0.03) with a yield of 84%.

[0216] 1 H NMR (400MHz, Methanol-d4) δ8.14(d,J=2.3Hz,2H),7.79-7.76(m,2H),7.11(d,J=8.3Hz,2H),2.71-2.60(m,2H),1.22(d,J=6.9Hz,12H)ppm. 13 C NMR (101MHz, Methanol-d4) δ178.7,170.8,139.5,139.1,132.6,132.0,123.5,122.2,37.0,19.9ppm.

[0217] Example 30

[0218]

[0219] Under a nitrogen atmosphere, 5-amino-2-bromobenzoic acid (4.629 mmol, 1 eq, 1 g), triethylamine (6.944 mmol, 1.5 eq, 0.7 g), and THF (15 mL) were added to the reaction flask. Finally, isohexanoyl chloride (5.1 mmol, 1.1 eq, 0.69 g) was slowly added at 0 °C. After stirring at 0 °C for 2–3 h, ethyl acetate (20 mL) and water (20 mL) were added for extraction. After standing and separation, the aqueous phase was discarded, and the organic phase was collected. The solvent was evaporated to dryness using a rotary evaporator. Finally, the target product was obtained by polar column chromatography using PE:EA (1:1) with a yield of 65%.

[0220] Weigh and add the prepared 2-bromo-5-(4-methylpentamido)benzoic acid (0.5 mmol, 1 eq, 143 mg), Mn (0.75 mmol, 1.5 eq, 42 mg), and 6,6'-dimethyl-2,2-bipyridine (0.08 mmol, 0.16 eq, 14.8 mg) to the reaction tube at room temperature. Then, transfer the reaction tube to a glove box and, under a nitrogen atmosphere, add t-BuOK (0.55 mmol, 0.55 eq, 62 mg) and NiCl2·dme (0.04 mmol, 0.08 eq, 8.7 mg), followed by 1.5 mL of DMF solvent. Stir at 40 °C for 2 h and monitor the reaction by TLC. After the reaction is complete, ethyl acetate (2 mL) and 2 mol / L HCl (2 mL) are added to quench the reaction. Subsequently, ethyl acetate (20 ml) and water (20 ml) were added for extraction. After standing and separating the layers, the aqueous phase was discarded, and fresh water (20 ml) was added again for extraction. The extraction process was repeated three times, and the organic phase was collected. The solvent was evaporated using a rotary evaporator, and finally, the target product was obtained by polar column chromatography using PE:EA:HCOOH (1:1:0.03) with a yield of 86%.

[0221] 1 H NMR(400MHz, Methanol-d4)δ8.13(d,J=2.3Hz,2H),7.78-7.75(m,2H),7.11(d, J=8.3Hz,2H),2.43-2.39(m,4H),1.68-1.58(m,6H),0.97(d,J=6.0Hz,12H)ppm. 13 C NMR (101MHz, Methanol-d4) δ175.0,170.9,139.5,139.0,132.6,132.1,123.4,122.1,36.1,35.8,29.1,22.7ppm.

Claims

1. A method for synthesizing 2,2'-biphenyl dicarboxylic acid compounds, characterized in that: Halogenated benzoic acid compounds undergo reductive coupling reaction with a metal reducing agent under the action of an alkaline and nickel catalyst / bident ligand composite catalytic system to obtain 2,2'-biphenyl dicarboxylic acid compounds; the bidentent ligand is 6,6'-dimethyl-2,2'-dipyridine; the conditions for the reductive coupling reaction are: reaction at 25~60℃ for 2~3h; The nickel catalyst is a nickel(II) chloride diethylene glycol dimethyl ether complex; The metal reducing agent is manganese; The alkali is t-BuOK; The reductive coupling reaction uses N,N-dimethylformamide as a solvent; The amount of nickel catalyst used is 8% of the molar amount of the halobenzoic acid compound; The amount of the bidentate ligand used is twice the molar amount of the nickel catalyst; The amount of the metal reducing agent is 1 to 3 times the molar amount of the halobenzoic acid compound; The ratio of the solvent to the halobenzoic acid compound is 0.5 mmol / 1.5 mL; The halobenzoic acid compounds have the structure of Formula 1: Formula 1; The 2,2'-biphenyl dicarboxylic acid compounds have the structure of Formula 2: Formula 2; in, X is a halogen substituent; R1 and R2 are independently selected from hydrogen and C. 1~10 aliphatic groups, C 1~10 Aliphatic derivative groups, C 1~10 Aliphatic ether groups, C 1~10 Aliphatic ether derivative groups, halogen substituents, C 2~10 Ester groups, sulfonic acid groups, silane ether groups, or amide groups.

2. The method for synthesizing a 2,2'-biphenyl dicarboxylic acid compound according to claim 1, characterized in that: The halogenated benzoic acid compounds are 2-iodobenzoic acid, 2-bromo-4-methylbenzoic acid, 2-bromo-4-tert-butylbenzoic acid, 2-bromo-4-methoxybenzoic acid, 2-bromo-4,5-difluorobenzoic acid, 2-bromo-5-fluorobenzoic acid, 2-chlorobenzoic acid, 2-bromo-6-(trifluoromethoxy)benzoic acid, 2-bromo-4-trifluoromethylbenzoic acid, 2-bromo-4-cyanobenzoic acid, 2-iodo-5-methylbenzoic acid, 2-iodo-5-methoxybenzoic acid, 2-iodo-5-fluorobenzoic acid, 2-iodo-4,5-dimethoxytoluic acid, and 5-chloro-2-iodobenzoic acid. 2-Iodo-5-trifluoromethylbenzoic acid, 2-Iodo-4,5-difluorobenzoic acid, 2-bromo-5-methoxybenzoic acid, 2-chloro-5-methoxybenzoic acid, 2-chloro-5-(methylthio)benzoic acid, 2-chloro-6-fluorobenzoic acid, 2-chloro-5-methylbenzoic acid, 2-chloro-4-methylsulfonylbenzoic acid, 2-chloro-6-(trifluoromethyl)benzoic acid, 2-bromo-4-fluoro-5-methylbenzoic acid, 6-bromo-2-fluoro-3-trifluoromethylbenzoic acid, 2-bromo-4-fluoro-5-methoxybenzoic acid, 2-bromo-3-methylbenzoic acid, 2-chloro-3-methylbenzoic acid, 2-Chloro-3-methoxybenzoic acid, 2-bromo-3-methoxybenzoic acid, 2-bromo-6-fluoro-3-methylbenzoic acid, 3-bromothiophene-2-carboxylic acid, 2-bromo-5-((tert-butyldimethylsilyl)oxy)benzoic acid, 2-bromo-5-((triisopropylsilyl)oxy)benzoic acid, 2-bromo-5-butoxybenzoic acid, 2-bromo-5-(isopentoxy)benzoic acid, 2-bromo-5-(2-ethylbutoxy)benzoic acid, 2-bromo-5-(cyclopropylmethoxy)benzoic acid, 2-bromo-5-(cyclobutylmethoxy)benzoic acid, 2-bromo-5-(cyclopropylmethoxy)benzoic acid, 2-bromo-5-(cyclobutylmethoxy)benzoic acid, 2-bromo-5-(cyclopropylmethoxy)benzoic acid Hexylmethoxy)benzoic acid, 2-bromo-5-(3-methoxypropoxy)benzoic acid, 2-bromo-5-((4-methylpent-3-en-1-yl)oxy)benzoic acid, 2-bromo-5-(4,4,4-trifluorobutoxy)benzoic acid, 2-bromo-5-(3-cyanopropoxy)benzoic acid, 2-bromo-5-(4-methylpentamido)benzoic acid, 2-bromo-5-(2-ethoxyacetamito)benzoic acid, 2-bromo-5-isobutamidobenzoic acid, 2-bromo-5-(cyclopentanecarboxamide)benzoic acid, or 2-bromo-4-((tert-butoxycarbonyl)amino)benzoic acid.

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