Preparation method of o-methoxybenzoic acid derivative

Abstract

The invention belongs to the field of organic synthetic chemistry, and particularly relates to a preparation method of an o-methoxybenzoic acid derivative, which comprises the following steps: carrying out ortho-position C-H bond methoxylation reaction on a compound 1 and methanol in the presence of a palladium catalyst, an oxidizing agent and alkali to generate the target product o-methoxybenzoic acid derivative in one step. Compared with the traditional synthesis method of the o-methoxybenzoic acid derivative, the innovative method has the advantages of short synthesis route, relatively mild conditions, wide substrate range and the like. And meanwhile, the used guiding group can be subjected to subsequent conversion, so that a molecular editing site is provided for subsequent derivatization reaction, and the chemical space of modular construction of drug molecules is greatly expanded.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthetic chemistry and specifically relates to a method for preparing o-anisic acid derivatives. The method utilizes a directing group-assisted carbon-hydrogen bond activation strategy to achieve direct methoxylation of ortho-CH bonds on aromatic rings, and is suitable for modular construction of o-anisic acid fragments in drug molecules. Background Art

[0002] o-Anisic acid and its derivatives are core structural units of a variety of drug molecules and are widely present in drugs for the treatment of intestinal diseases, diabetes and mental illnesses. The pharmacological activity of such compounds is closely related to their ortho-methoxy substitution pattern, but the synthesis of complex derivatives still faces significant challenges. Traditional synthetic methods mainly rely on pre-activation strategies: 1. Introduction of strong electron-withdrawing groups: A fluorine atom needs to be introduced as a leaving group at the target site of the aromatic ring, and a strong electron-withdrawing group such as a nitro group or a trifluoromethyl group needs to be introduced at its ortho or para position to activate the CF bond. Subsequently, methoxylation is achieved through nucleophilic aromatic substitution (SNAr) of the methoxy anion. 2. Defect analysis: (1) Substrate limitations: only applicable to aromatic rings containing strong electron-withdrawing groups, substrates containing electron-donating or weak electron-withdrawing groups cannot react; (2) Harsh conditions: high temperature (>150°C) and strong base (such as NaOH / EtOH system) are required, resulting in the decomposition of heat-sensitive or base-sensitive functional groups (such as ester groups and amides); (3) Many by-products: side reactions such as decarboxylation and aromatic ring opening are prone to occur at high temperatures; (4) Poor atom economy: additional pre-activated groups (such as nitro groups) need to be introduced and removed, resulting in multi-step reactions and resource waste. The above defects seriously restrict the rapid construction of o-anisic acid compounds and the functional modification of drug molecules. Therefore, there is an urgent need to develop a synthetic method with mild conditions, universal substrate compatibility, and high atom efficiency. Summary of the Invention

[0003] The present invention aims to overcome the shortcomings of the prior art and provide a method for preparing o-anisic acid derivatives that can directly achieve methoxylation of the ortho-CH bond of the aromatic ring, has high substrate applicability, mild reaction conditions, provides molecular editing sites for subsequent derivatization, has ideal drug molecule scalability, and meets the requirements of green chemistry.

[0004] To solve the above-mentioned technical problems, the present invention is achieved as follows:

[0005] A method for preparing o-anisic acid derivatives comprises the following steps: reacting compound 1 with methanol in the presence of a palladium catalyst, an oxidant, and a base in a solvent system other than methanol, or using only methanol as the solvent, to carry out ortho-CH methoxylation reaction to produce the target o-anisic acid derivative in one step.

[0006] Furthermore, the compound 1 is a benzoic acid derivative containing a methoxyoxime amide directing group, and its specific structure is as follows:

[0007]

[0008] Wherein, R is selected from F, Cl, Br, CF3, NO2, CN, CO2Me, Me, t Bu, OMe or O t Bu.

[0009] Furthermore, the palladium catalyst is selected from one or a mixture of two or more of Pd(OAc)2, Pd(TFA)2, Pd(OPiv)2, PdCl2, PdBr2 and PdI2.

[0010] Furthermore, the oxidant is selected from one or a mixture of two or more of PhI(OAc)2, PhI(TFA)2 and PhI(OPiv)2.

[0011] Furthermore, the base is selected from one or a mixture of two or more of LiOH, NaOH, KOH, CsOH, Li2CO3, Na2CO3, K2CO3 and Cs2CO3.

[0012] Furthermore, the reaction temperature of the ortho-CH bond methoxylation is 60-130° C., and the reaction is carried out under oxygen-free and water-free conditions.

[0013] Furthermore, the solvent other than methanol is 1,2-dichloroethane, toluene, o-xylene, m-xylene, and p-xylene.

[0014] Furthermore, in the solvent system other than methanol, the molar ratio of compound 1 to the solvent is 1:5; if only methanol is used as the solvent, the molar ratio of compound 1 to methanol is 1:100-250; the reaction temperature of the ortho-CH bond methoxylation is 78-82°C.

[0015] Furthermore, the molar ratio of the palladium catalyst, the oxidant and the base is 0.1:2-10:1-5.

[0016] The o-anisic acid derivatives prepared by the above method have a structure as shown in Formula I:

[0017]

[0018] Wherein, R is selected from F, Cl, Br, CF3, NO2, CN, CO2Me, Me, t Bu, OMe or O t Bu.

[0019] The synthesis mechanism of the present invention is as follows:

[0020]

[0021] The present invention uses a directing group-assisted carbon-hydrogen bond activation strategy. By directing the conversion of the carboxyl group of the benzoic acid skeleton into a methoxy oxime amide directing group and utilizing its ortho-position regioselectivity, the direct methoxylation of the ortho-CH bond of the aromatic ring is successfully achieved, and an o-anisic acid derivative is constructed. The present invention simplifies the synthesis route by using a specific positioning directing group, abandons the traditional electron-withdrawing introduction step, and achieves "one-step" precise methoxylation. No longer using strong base and high temperature conditions, the substrate universality of the original route is improved, and it can tolerate a variety of functional groups including electron-donating groups, electron-withdrawing groups and halogens, as well as functional groups that are not resistant to strong base conditions. In addition, the atomic utilization rate of the directing group is high, which reduces by-products, and can also be further derivatized by the directing group to form a variety of structural types of products, which can be used as a synthesis method for o-anisic acid derivatives. First, the present invention's compound 1 (a benzoic acid derivative containing a directing group) reacts with methanol in the presence of a palladium catalyst, an oxidant, and a base to undergo ortho-CH methoxylation to produce the target product (Formula I) in one step. Secondly, the directing group can be further converted into other functional groups (such as carboxylic acids and amides), achieving molecular diversification. Compared with existing technologies, the present invention has the following advantages:

[0022] (1) Directly methoxylate the ortho-CH bonds of the aromatic rings through a directing group-assisted carbon-hydrogen bond activation strategy, eliminating the traditional pre-activation step and achieving "one-step" precise methoxylation. The present invention uses a directing group-assisted carbon-hydrogen bond activation strategy to direct the conversion of the carboxyl group of the benzoic acid skeleton into a methoxyoxime amide directing group, utilizing its ortho-regioselectivity to achieve direct methoxylation of the ortho-CH bonds of the aromatic rings and construct o-methoxybenzoic acid derivatives;

[0023] (2) Improve substrate applicability and compatibility with electron-donating groups, electron-withdrawing groups, halogens, and base-sensitive functional groups (such as cyano and ester groups); successfully applied to substrates containing functional groups such as -Cl, -CF3, -OMe, and -CN;

[0024] (3) Reduce the severity of the reaction conditions, avoid high temperature and strong alkaline environment, and reduce the formation of by-products; react at a medium temperature of 80°C to avoid high temperature side reactions;

[0025] (4) Through the design of multifunctional directing groups (such as methoxyoxime amide), molecular editing sites are provided for subsequent derivatization, thereby expanding the diversity of drug molecules; methoxyoxime amide can be converted into carboxylic acids, amides, etc., supporting the modular construction of drug molecules;

[0026] (5) Achieve atom-economical synthesis, retain the directing group in the product, reduce waste emissions, and meet the requirements of green chemistry. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The present invention will be described in detail below through specific examples. These examples are provided in order to enable a more thorough understanding of the present invention and to fully convey the scope of the present invention to those skilled in the art. As mentioned throughout the specification and claims, "including" or "comprising" is an open-ended term and is interpreted as "including but not limited to". The subsequent description of the specification is a preferred embodiment of the present invention, but the description is based on the general principles of the specification and is not intended to limit the scope of the present invention. The scope of protection of the present invention shall be determined by the appended claims. Unless otherwise specified, the various reagents and materials used in the present invention can be purchased from the market.

[0028] Figure 1 Schematic diagram comparing the traditional SNAr reaction and the present invention. DETAILED DESCRIPTION

[0029] Example 1 (optimal conditions, system with only methanol as solvent):

[0030] Compound 1-a (0.1mmol, 1.0eq, 26.9mg), Pd(OAc)2 (0.01mmol, 0.1eq, 2.4mg), PhI(OAc)2 (0.5mmol, 5.0eq, 161.0mg), NaOH (0.2mmol, 2.0eq, 8.0mg) and 1ml of methanol (24.7mmol, 247.2eq) were placed in a sealed tube of appropriate size and argon was continuously introduced for 1 minute. After the ventilation was completed, the system was placed in a metal bath at 80°C for 24 hours. After the reaction was completed, TLC was used for monitoring. After the sealed tube was cooled to room temperature, the reaction system was poured into a sand core funnel filled with diatomaceous earth, the reaction system was filtered, and rinsed with dichloromethane until the diatomaceous earth contained no product. The system was then concentrated under reduced pressure using a rotary evaporator and then purified by column chromatography using petroleum ether:ethyl acetate = 10:1 as the eluent. After column chromatography purification, the corresponding ortho-methoxylated product I-1 was obtained.

[0031]

[0032] I-1: transparent oily liquid (83%); 1 H NMR (400MHz, CDCl3) δ = 7.22 (t, J = 8.2Hz, 1H), 6.95 (d, J = 8.0Hz, 1H), 6.80 (d, J =8.4, 1H), 6.77 (br, 1H), 3.83 (s, 3H), 3.80 (s, 3H), 1.89 (s, 3H), 1.63 (s, 6H); 13C NMR (101MHz, CDCl3) δ = 163.8, 159.2, 157.4, 132.0, 130.3, 127.2, 121.7, 109.6, 61.7, 57.4, 56.2, 24.8, 10.2; HRMS (ESI) m / z calcd.for C 14 H 20 ClN2O3 + [M+H + ]: 299.1157, found: 299.1158.

[0033] Example 2:

[0034] Compound 1-a (0.1mmol, 1.0eq, 26.9mg), Pd(OAc)2 (0.01mmol, 0.1eq, 2.4mg), PhI(OAc)2 (0.5mmol, 5.0eq, 161.0mg), NaOH (0.2mmol, 2.0eq, 8.0mg) and methanol (0.5mmol, 5.0eq, 20μL) and 1ml of 1,2-dichloroethane were taken into a sealed tube of appropriate size, and argon was continuously introduced for 1 minute. The mixture was placed in a metal bath at 80°C for 24 hours. After the reaction was completed, TLC was used for monitoring. After the sealed tube was cooled to room temperature, the reaction system was poured into a sand core funnel filled with diatomaceous earth, the reaction system was filtered, and rinsed with dichloromethane until the diatomaceous earth contained no product. The system was then concentrated under reduced pressure using a rotary evaporator and then purified by column chromatography using petroleum ether:ethyl acetate = 10:1 as the eluent. After column chromatography purification, the corresponding ortho-methoxylated product I-1 was obtained with a yield of 61%.

[0035] Example 3:

[0036] Compound 1-a (0.1mmol, 1.0eq, 26.9mg), Pd(OAc)2 (0.01mmol, 0.1eq, 2.4mg), PhI(OAc)2 (0.5mmol, 5.0eq, 161.0mg), NaOH (0.2mmol, 2.0eq, 8.0mg) and methanol (0.5mmol, 5.0eq, 20μL) and 1ml of toluene were taken into a sealed tube of appropriate size, and argon was continuously introduced for 1 minute. The mixture was placed in a metal bath at 80°C for 24 hours. After the reaction was completed, TLC was used for monitoring. After the sealed tube was cooled to room temperature, the reaction system was poured into a sand core funnel filled with diatomaceous earth, the reaction system was filtered, and rinsed with dichloromethane until the diatomaceous earth contained no product. The system was then concentrated under reduced pressure using a rotary evaporator and then purified by column chromatography using petroleum ether:ethyl acetate = 10:1 as the eluent. After column chromatography purification, the corresponding ortho-methoxylated product I-1 was obtained with a yield of 64%.

[0037] Example 4:

[0038] Compound 1-a (0.1mmol, 1.0eq, 26.9mg), Pd(OAc)2 (0.01mmol, 0.1eq, 2.4mg), PhI(OAc)2 (0.5mmol, 5.0eq, 161.0mg), NaOH (0.2mmol, 2.0eq, 8.0mg) and methanol (0.5mmol, 5.0eq, 20μL) and 1ml of o-xylene were taken into a sealed tube of appropriate size, and argon was continuously introduced for 1 minute. The mixture was placed in a metal bath at 80°C for 24 hours. After the reaction was completed, TLC was used for monitoring. After the sealed tube was cooled to room temperature, the reaction system was poured into a sand core funnel filled with diatomaceous earth, the reaction system was filtered, and rinsed with dichloromethane until the diatomaceous earth contained no product. The system was then concentrated under reduced pressure using a rotary evaporator and then purified by column chromatography using petroleum ether:ethyl acetate = 10:1 as the eluent. After column chromatography purification, the corresponding ortho-methoxylated product I-1 was obtained with a yield of 51%.

[0039] Examples 5 to 18:

[0040] Under the reaction conditions of Example 1, by using compounds 1 containing different substituents as raw materials, namely 1-b to 1-o, 14 additional derivatives (total 15 including 1-a) were synthesized with yields of 45-84%. 1 H NMR, 13 C NMR and HRMS confirmed.

[0041] Example 5:

[0042]

[0043] I-2: transparent oily liquid (73%); 1 H NMR (400MHz, CDCl3) δ = 7.24 (t, J = 8.4Hz, 1H), 6.95 (d, J = 8.0Hz, 1H), 6.77 (br, 1 H), 6.80 (d, J=8.4Hz, 2H), 3.83 (s, 3H), 3.79 (s, 3H), 1.90 (s, 3H), 1.61 (s, 6H); 13 C NMR (101MHz, CDCl3) δ = 164.8, 159.8, 157.6, 130.4, 117.0, 104.2, 61.7, 57.1, 56.1, 25.1, 10.2; HRMS (ESI) m / z calcd.for C 15 H 23 N2O4 +[M+H + ]: 295.1652, found: 295.1650.

[0044] Example 6:

[0045]

[0046] I-3: yellow oily liquid (80%); 1 H NMR (400MHz, CDCl3) δ=7.42 (t, J=8.0Hz, 1H), 7.23 (d, J=8.0Hz, 1H), 7.10 (d, J= 8.4Hz, 1H), 6.89(br, 1H), 3.85(s, 3H), 3.81(s, 3H), 1.88(s, 3H), 1.63(s, 6H); 13 C NMR (101MHz, CDCl3) δ163.7, 159.1, 157.1, 130.2, 128.6 (q, J=31.8Hz), 126.2 (q, J=2.1Hz), 1 23.6 (q, J=263.0Hz), 118.0 (q, J=5.1Hz) 114.9, 61.8, 57.5, 56.4, 24.3, 10.1.; HRMS (ESI) m / z calcd.for C 15 H 20 F3N2O3 + [M+H + ]: 333.1421, found: 333.1422.

[0047] Example 7:

[0048]

[0049] I-4: yellow oily liquid (75%); 1 H NMR (400MHz, CDCl3) δ = 7.18-7.12 (m, 2H), 6.84 (d, J = 7.2Hz, 1H), 6.75 (br, 1H ), 6.80 (d, J=8.4Hz, 2H), 3.83 (s, 3H), 3.81 (s, 3H), 1.90 (s, 3H), 1.65 (s, 6H); 13 C NMR (101MHz, CDCl3) δ = 164.6, 159.2, 157.5, 130.7, 129.3, 124.9, 120.7, 110.2, 61.8, 57.4, 56.3, 24.7, 10.3; HRMS (ESI) m / z calcd.for C 14 H 20 BrN2O3+ [M+H + ]: 343.0652, found: 343.0654.

[0050] Example 8:

[0051]

[0052] I-5: yellow oily liquid (78%); 1 H NMR (400MHz, CDCl3) δ = 7.29-7.23 (m, 1H), 7.03 (br, 1H), 6.72-6.68 (m, 2H), 6.80(d, J=8.4Hz, 2H), 3.84(s, 3H), 3.83(s, 3H), 1.88(s, 3H), 1.63(s, 6H); 13 C NMR (101MHz, CDCl3) δ=161.8, 161.5 (d, J=248.2Hz), 157.9 (d, J=29.2Hz), 130.9 (d, J=40.8Hz), 130.9 (d, J=40.8 Hz) 115.9 (d, J=78.0Hz), 108.5 (d, J=89.6Hz), 107.0 (d, J=12.0Hz), 61.7, 57.4, 56.4, 24.8, 10.2; HRMS (ESI) m / z calcd.for C 14 H 20 FN2O3 + [M+H + ]: 283.1452, found: 283.1449.

[0053] Example 9:

[0054]

[0055] I-6: yellow oily liquid (45%); 1 H NMR (400MHz, CDCl3) δ = 7.03 (dd, J = 11.2, 9.6Hz, 1H), 6.71 (br, 1H), 6.54 (dd, J = 9.2, 3.2 Hz, 1H), 3.94 (s, 3H), 3.94 (s, 3H), 3.84 (s, 3H), 3.78 (s, 3H), 1.90 (s, 3H), 1.63 (s, 6H); 13C NMR (101MHz, CDCl3) δ163.3 (d, J=2.4Hz), 159.4, 152.9 (d, J=2.1Hz), 151.1 (d, J=242.1Hz), 145.4 (d, J=13.1Hz), 1 22.9, 116.9 (d, J = 20.5Hz), 106.32 (d, J = 6.9Hz), 62.3, 62.2, 61.8, 57.3, 56.5, 24.9, 10.2; HRMS (ESI) m / zcalcd.for C 15 H 22 FN2O4 + [M+H + ]:313.1558, found:313.1559.I-6a:transparent oily liquid (20%); 1 HNMR (400MHz, CDCl3) δ=7.11 (t, J=9.2Hz, 1H), 7.03 (br, 1H), 6.74 (d, J=9.2, 3.6Hz, 1H), 3.85(s, 3H), 3.82(s, 3H), 2.29(s, 3H), 1.86(s, 3H), 1.60(s, 6H); HRMS(ESI)m / z calcd.forC 16 H 22 FN2O5 + [M+H + ]: 341.1507, found: 341.1508.

[0056] Example 10:

[0057]

[0058] I-7: transparent oily liquid (69%); 1 H NMR (400MHz, CDCl3) δ=7.36 (t, J=8.8Hz, 1H), 6.94 (br, 1H), 6.77 (d, J=8.8Hz, 1H) ,3.84(s,3H),3.82(s,3H),2.29(s,3H),1.85(s,3H),1.58(s,6H).HRMS(ESI)m / z calcd.for C 16 H 22 ClN2O5 + [M+H + ]: 357.1212, found: 357.1215.

[0059] Example 11:

[0060]

[0061] I-8: light yellow oily liquid (74%); 1 H NMR (400MHz, CDCl3) δ=6.90 (d, J=8.8Hz, 1H), 6.82 (br, 1H), 6.74 (d, J=8.8Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H), 2.26 (s, 3H), 1.86 (s, 3H), 1.57 (s, 6H); HRMS (ESI) m / z calcd.for C 17 H 25 N2O5 + [M+H + ]: 337.1758, found: 337.1759.

[0062] Example 12:

[0063]

[0064] I-9: pale yellow oily liquid (64%); 1 H NMR (400MHz, CDCl3) δ=7.17 (d, J=8.4Hz, 1H), 6.86 (br, 1H), 6.74 (d, J=8.4Hz, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 2.28 (s, 3H), 2.09 (s, 3H), 1.87 (s, 3H), 1.58 (s, 6H); HRMS (ESI) m / z calcd.for C 17 H 25 N2O6 + [M+H + ]: 353.1707, found: 353.1708.

[0065] Example 13:

[0066]

[0067] I-10: light yellow oily liquid (84%); 1 H NMR (400MHz, CDCl3) δ = 6.77 (s, 2H), 6.72 (br, 1H), 6.72 (s, 1H), 3.84 (s, 6H), 3.83 (s, 3H), 1.89 (s, 3H), 1.63 (s, 6H); 13C NMR (101MHz, CDCl3) δ=163.4, 159.4, 157.7, 132.5 (q, J=32.6Hz), 123.8 (q, J=27 3.8Hz), 119.8, 101.4 (q, J=3.8Hz), 61.8, 57.3, 56.4, 24.9, 10.2; HRMS (ESI) m / z calcd.for C 16 H 22 F3N2O4 + [M+H + ]: 363.1526, found: 363.1528.

[0068] Example 14:

[0069]

[0070] I-11: yellow oily liquid (76%); 1 H NMR (400MHz, CDCl3) δ = 6.81 (s, 2H), 6.76 (br, 1H), 3.82 (s, 9H), 1.87 (s, 3H), 1.62 (s, 6H); 13 C NMR (101MHz, CDCl3) δ = 162.7, 159.2, 157.6, 121.3, 118.6, 113.7, 108.1, 61.8, 57.4, 56.5, 24.8, 10.2; HRMS (ESI) m / z calcd.forC 16 H 22 N3O4 + [M+H + ]: 320.1605, found: 320.1604.

[0071] Example 15:

[0072]

[0073] I-12: transparent oily liquid (80%); 1 H NMR (400MHz, CDCl3) δ = 7.20 (s, 2H), 6.79 (br, 1H), 6.72 (s, 1H), 3.90 (s, 3H), 3.83 (s, 6H), 3.81 (s, 3H), 1.88 (s, 3H), 1.61 (s, 6H); 13C NMR (101MHz, CDCl3) δ = 166.5, 163.9, 159.5, 157.3, 131.9, 120.8, 105.4, 61.7, 57.2, 56.3, 52.5, 25.0, 10.1; HRMS (ESI) m / z calcd.for C 17 H 25 N2O6 + [M+H + ]: 353.1707, found: 353.1705.

[0074] Example 16:

[0075]

[0076] I-13: transparent oily liquid (72%); 1 H NMR (400MHz, CDCl3) δ = 6.61 (s, 2H), 6.09 (br, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 3.79 (s, 6H), 1.89 (s, 3H), 1.60 (s, 6H); 13 C NMR (101MHz, CDCl3) δ164.7, 161.9, 159.9, 158.7, 110.2, 90.8, 61.7, 57.1, 56.1, 55.6, 25.1, 10.2; HRMS (ESI) m / zcalcd.for C 16 H 25 N2O5 + [M+H + ]: 325.1758, found: 325.1759.

[0077] Example 17:

[0078]

[0079] I-14: transparent oily liquid (79%); 1 H NMR (400MHz, CDCl3) δ = 6.57 (br, 1H), 6.35 (s, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 2.33 (s, 3H), 1.89 (s, 3H), 1.60 (s, 6H); 13 C NMR (101MHz, CDCl3) δ165.0, 159.9, 157.5, 140.9, 114.3, 105.0, 61.7, 57.1, 56.1, 25.1, 22.3, 10.2; HRMS (ESI) m / z calcd.for C 16 H25 N2O4 + [M+H + ]: 309.1809, found: 309.1810.

[0080] Example 18:

[0081]

[0082] I-15: transparent oily liquid (67%); 1 H NMR (400MHz, CDCl3) δ = 6.56 (s, 2H), 6.54 (br, 1H), 3.84 (s, 3H), 3.81 (s, 6H), 1.90 (s, 3H), 1.60 (s, 6H), 1.31 (s, 9H); 13 C NMR (101MHz, CDCl3) δ = 165.0, 160.0, 157.3, 154.4, 114.6, 101.8, 61.7, 57.1, 56.1, 35.5, 31.4, 25.2, 10.2; HRMS (ESI) m / z calcd.for C 19 H 31 N2O4 + [M+H + ]: 351.2278, found: 351.2279.

[0083] It can be understood that the above specific description of the present invention is only used to illustrate the present invention and is not limited to the technical solutions described in the embodiments of the present invention. Those skilled in the art should understand that the present invention can still be modified or replaced by equivalents to achieve the same technical effects; as long as the use requirements are met, they are within the scope of protection of the present invention.

Claims

1. A method for preparing o-anisic acid derivatives, characterized in that: The method comprises the following steps: performing a methoxylation reaction of the ortho-CH bond of compound 1 with methanol in the presence of a palladium catalyst, an oxidant and a base in a solvent system other than methanol, or using only methanol as a solvent, to generate the target product, an o-anisic acid derivative, in one step.

2. The method for preparing o-anisic acid derivatives according to claim 1, wherein: The compound 1 is a benzoic acid derivative containing a methoxyoxime amide directing group, and its specific structure is as follows: Wherein, R is selected from F, Cl, Br, CF3, NO2, CN, CO2Me, Me, t Bu, OMe or O t Bu.

3. The method for preparing o-anisic acid derivatives according to claim 2, wherein: The palladium catalyst is selected from one or a mixture of two or more of Pd(OAc)2, Pd(TFA)2, Pd(OPiv)2, PdCl2, PdBr2 and PdI2.

4. The method for preparing o-anisic acid derivatives according to claim 3, wherein: The oxidant is selected from one or a mixture of two or more of PhI(OAc)2, PhI(TFA)2 and PhI(OPiv)2.

5. The method for preparing o-anisic acid derivatives according to claim 4, characterized in that: The base is selected from one or a mixture of two or more of LiOH, NaOH, KOH, CsOH, Li2CO3, Na2CO3, K2CO3 and Cs2CO3.

6. The method for preparing o-anisic acid derivatives according to claim 5, characterized in that: The reaction temperature of the ortho-CH bond methoxylation is 60-130° C., and the reaction is carried out under oxygen-free and water-free conditions.

7. The method for preparing o-alkoxybenzoic acid derivatives according to claim 6, characterized in that: The solvent other than methanol is 1,2-dichloroethane, toluene, o-xylene, m-xylene, and p-xylene.

8. The method for preparing o-anisic acid derivatives according to claim 7, characterized in that: In the solvent system of compound 1 and methanol other than methanol, the molar ratio of compound 1 to the solvent is 1:5; if only methanol is used as the solvent, the molar ratio of compound 1 to methanol is 1:100-250; the reaction temperature of the ortho-CH bond methoxylation is 78-82°C.

9. The method for preparing o-anisic acid derivatives according to claim 8, characterized in that: The molar ratio of the palladium catalyst, the oxidant and the base is 0.1:2-10:1-5.

10. An o-anisic acid derivative prepared by the method according to any one of claims 1 to 9, characterized in that: Its structure is shown in Formula I: Wherein, R is selected from F, Cl, Br, CF3, NO2, CN, CO2Me, Me, t Bu, OMe or O t Bu.

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