Preparation method of 2, 4-difluoro-3-methoxybenzoic acid

Abstract

The invention discloses a preparation method of 2, 4-difluoro-3-methoxybenzoic acid, belongs to the technical field of organic synthesis, and solves the problems of high production cost and difficulty in industrialization in the prior art. The preparation method comprises the following steps: S1, carrying out a halogenation reaction on a compound Ia to generate a compound Ib, S2, carrying out diazotization on the compound Ib, and hydrolyzing to obtain a compound Ic, S3, carrying out a methylation reaction on the compound Ic to generate a compound Id, and S4, reacting the compound Id with carbon dioxide under the action of a Grignard reagent to generate a compound I 2, 4-difluoro-3-methoxybenzoic acid. The synthetic route is shown in the specification. According to the invention, the problems of need of a lithium reagent and low-temperature reaction are avoided by introducing a halogen positioning method; meanwhile, the compound Id can be directly used for subsequent reaction steps without rectification and purification. The method has the advantages of low raw material price, no positional isomer, high yield, good reaction safety, simplicity and convenience in operation and easiness in industrial production. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 2,4-difluoro-3-methoxybenzoic acid. Background Art

[0002] Quinolone drugs are a class of antibiotics widely used clinically and have now developed to the fourth generation. Among them, the third and fourth generations of fluoroquinolones significantly enhance the antibacterial activity against common pathogenic bacteria such as Streptococcus pneumoniae in respiratory tract infections, and at the same time have good antimicrobial activity against atypical pathogens such as Mycoplasma pneumoniae and Chlamydia pneumoniae. Representative varieties include levofloxacin and moxifloxacin, which are both called "respiratory quinolones". In recent years, new non-fluorinated quinolone drugs, such as ganofloxacin and nemonoxacin, have also been applied clinically.

[0003] In the synthesis of nemonoxacin in the prior art, there is a very crucial material, namely 2,4-difluoro-3-methoxybenzoic acid. However, in the synthesis of this material in the prior art, most of them use ultra-low temperature and relatively dangerous lithium reagents, etc., resulting in high requirements for reaction equipment, and at the same time, the reaction is more dangerous, which limits the industrial production of this route.

[0004] For example, Patent CN101263146 discloses that it reacts with carbon dioxide at -78°C under the action of lithium diisopropylamide to generate 2,4-difluoro-3-methoxybenzoic acid, and this route method uses lithium diisopropylamide and an ultra-low temperature reaction condition of -78°C.

[0005] Patent CN103819401 discloses a method for preparing 2,4-difluoro-3-methoxybenzoic acid from m-difluorobenzene through 4 steps. This route experiences the reaction of lithium reagent with borate at -60 to -70°C, and also experiences the reaction of lithium reagent at -78°C. This route involves two ultra-low temperature reactions and uses relatively dangerous lithium reagents. In addition, the compound difluorophenyl methyl ether in this route needs to be purified by rectification, which has high requirements for the performance of the equipment, and a large amount of waste water and waste gas will be generated during the rectification process, further increasing the production cost.

[0006] Therefore, providing a preparation method of 2,4-difluoro-3-methoxybenzoic acid, a key intermediate of nemonoxacin, with low production cost and easy industrialization has become an urgent problem to be solved by those skilled in the art. Summary of the Invention

[0007] The purpose of the present invention is to provide a preparation method of 2,4-difluoro-3-methoxybenzoic acid to solve the problems of high production cost and difficulty in industrialization in the prior art.

[0008] To achieve the above purpose, the technical scheme adopted by the present invention is as follows:

[0009] A method for preparing 2,4-difluoro-3-methoxybenzoic acid disclosed by the present invention comprises the following steps:

[0010] S1. Compound Ia undergoes a halogenation reaction to generate compound Ib,

[0011] S2. Compound Ib is diazotized and then hydrolyzed to obtain compound Ic,

[0012] S3. Compound Ic undergoes a methylation reaction to generate compound Id,

[0013] S4. Compound Id reacts under the action of a Grignard reagent to generate compound I;

[0014] Its synthesis route is as follows:

[0015]

[0016] In some embodiments of the present invention, in step S1, compound Ia reacts with a halogenating reagent under sulfuric acid conditions to generate compound Ib.

[0017] In some embodiments of the present invention, the halogenating reagent includes at least one of N-bromosuccinimide, bromine or N-chlorosuccinimide;

[0018] In some embodiments of the present invention, the molar ratio of compound Ia to the halogenating reagent is 1:1 to 1:4; preferably 1:1 to 2; more preferably 1:1.35 to 1.8;

[0019] In some embodiments of the present invention, the molar ratio of compound Ia to the brominating reagent is 1:1.1 to 1.8;

[0020] In some embodiments of the present invention, the molar ratio of compound Ia to the chlorinating reagent is 1:1.5 to 1.3;

[0021] In some embodiments of the present invention, the temperature of the halogenation reaction is 15 to 60 °C; preferably 15 to 30 °C;

[0022] In some embodiments of the present invention, 0.5 - 1.2 L of sulfuric acid is added per 1 mol of compound Ia, preferably 0.625 - 1 L.

[0023] In some embodiments of the present invention, in step S2, compound Ib reacts with a nitrite to generate a diazonium salt, and then undergoes hydrolysis to obtain compound Ic.

[0024] In some embodiments of the present invention, in step S2, the nitrite includes at least one of sodium nitrite and potassium nitrite;

[0025] In some embodiments of the present invention, the molar ratio of compound Ib to nitrite is 1:1 to 1:2; preferably 1:1 - 1.5.

[0026] In some embodiments of the present invention, compound Ib reacts with nitrite under acidic conditions, preferably in an aqueous sulfuric acid solution, more preferably in an aqueous sulfuric acid solution with a concentration of 3 - 8 wt.%.

[0027] In some embodiments of the present invention, after the diazonium salt reaction is completed, the system is added to a mixed solution of a first organic solvent and water. The first organic solvent includes at least one of dichloromethane, tetrahydrofuran, 1,2 - dichloroethane, toluene, ethyl acetate, 2 - methyltetrahydrofuran, sulfolane, cyclopentyl methyl ether, and isopropanol. In the mixed solution, the ratio of the first organic solvent to water is 1:0.5 to 1:4, preferably 1:0.5 to 1:1.5.

[0028] In some embodiments of the present invention, compound Ib reacts with nitrite under low - temperature conditions, preferably - 5 to 10 °C, more preferably 0 to 5 °C.

[0029] In some embodiments of the present invention, after the diazonium salt reaction is completed, the system is heated to form compound Ic, preferably at the reflux temperature.

[0030] In some embodiments of the present invention, in step S3, compound Ic reacts with a methylation reagent under basic conditions to form compound Id.

[0031] In some embodiments of the present invention, in step S3, the methylation reagent includes at least one of methyl iodide and dimethyl sulfate.

[0032] In some embodiments of the present invention, the molar ratio of compound Ic to the methylation reagent is 1:5, preferably 1:1 - 3.5, more preferably 1:1.6 - 3.15.

[0033] Preferably, the basic substance includes at least one of sodium carbonate, potassium carbonate, magnesium hydroxide, aluminum hydroxide, zinc hydroxide, copper hydroxide, ammonia water, sodium bicarbonate, potassium bicarbonate, sodium acetate, potassium acetate, and cesium carbonate.

[0034] Preferably, the molar ratio of compound Ic to the basic substance is 1:1.5 - 5; preferably 1:3.

[0035] Preferably, a basic substance and a methylation reagent are added to compound Ic, and then the temperature is raised for the reaction.

[0036] Preferably, the solvent of compound Ic includes at least one of acetone, tetrahydrofuran, methanol, ethanol, and isopropanol.

[0037] More preferably, the reaction is carried out at room temperature or at reflux.

[0038] In some embodiments of the present invention, in step S4, the Grignard reagent comprises a C1-C4 magnesium halide reagent, wherein the halogen comprises chlorine or bromine;

[0039] In some embodiments of the present invention, in step S4, the Grignard reagent includes at least one of methylmagnesium chloride and isopropylmagnesium chloride;

[0040] In some embodiments of the present invention, in step S4, the molar ratio of compound Id to Grignard reagent is 1:0.8-1.5; preferably 1:1.1-1.3;

[0041] Preferably, compound Id is first reacted with a Grignard reagent, and then carbon dioxide is introduced to react;

[0042] Preferably, compound Id is first reacted with a Grignard reagent at low temperature and protective gas conditions, and then carbon dioxide is introduced and the temperature is raised to react;

[0043] Preferably, compound Id is first reacted with a Grignard reagent at -40 to 20°C, preferably -20 to 0°C, and then carbon dioxide is introduced and the reaction is continued at a temperature of -40 to 20°C.

[0044] In some embodiments of the present invention, in step S4, the organic solvent in the Grignard reagent comprises at least one of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, benzene, and acetonitrile.

[0045] In some embodiments of the present invention, in step S4, the organic solvent in the Grignard reagent is tetrahydrofuran.

[0046] In some embodiments of the present invention, a post-treatment step is further included: in step S4, after the reaction is completed, ice water is slowly added dropwise to the system to concentrate the reaction solution, an organic solvent and an alkaline aqueous solution are added to the residue, and the pH value of the aqueous phase is adjusted to acidic to precipitate solids.

[0047] Preferably, the organic solvent comprises ethyl acetate;

[0048] Preferably, the alkaline aqueous solution is a sodium hydroxide aqueous solution;

[0049] Preferably, after the aqueous phase is washed with the third organic solvent, hydrochloric acid is added to adjust the pH value to ≤2.

[0050] Compared with the prior art, the present invention has the following beneficial effects:

[0051] This invention is scientifically designed and ingeniously conceived. By introducing a halogen-positioned method, it circumvents the problems of lithium reagents and low-temperature reactions in the prior art. Compound Id also does not require distillation purification and can be used directly in subsequent reaction steps. The starting material, Compound Ia (2,5-difluorobenzylamine), is commercially available at a lower price than the prior art starting material, Compound IIa (m-difluorobenzene), and is free of positional isomers. The overall reaction yield and reagent costs are superior to those of the prior art, while the reaction is highly safe, simple to operate, and amenable to industrial production. DETAILED DESCRIPTION

[0052] To make the purpose, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention will be described clearly and completely below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer are followed. Where the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0053] The Chinese equivalents of the English versions of the embodiments of the present invention are as follows:

[0054] THF: tetrahydrofuran.

[0055] Example 1

[0056] This example discloses a method for preparing compound I, and the process route is as follows:

[0057]

[0058] ; The specific steps are:

[0059] (1) Preparation of compound Ib-1:

[0060] To 258.22 g of compound Ia was added 1.25 L of sulfuric acid, and 480.55 g of N-bromosuccinimide was added at 20-30° C. The reaction was continued with stirring. After the reaction was completed, the system was poured into ice water. A large amount of white solid precipitated in the system, which was filtered and the filter cake was dried to obtain 384.00 g of compound Ib-1 with a yield of 92.31% (M+H). + =207.96,209.95.

[0061] (2) Preparation of compound Ic-1:

[0062] To 208.00 g of compound Ib-1, 1.0 L of 5 wt.% sulfuric acid aqueous solution was added. 800 ml of an aqueous solution containing 79.35 g of sodium nitrite was added dropwise at 0 - 5 °C. After the reaction was completed, the system was added to a mixed solution containing 2 L of cyclopentyl methyl ether and 1 L of purified water. Then the system was heated to reflux for reaction. After the reaction was complete, ethyl acetate was added to the reaction system for extraction. After concentration of the organic phase, 245 g of compound Ic-1 was obtained, with a yield of 117%. Compound Ic-1 is a needle-like solid, [M + H] + = 208.94, 210.94.

[0063] (3) Preparation of compound Id-1:

[0064] To 220 g of compound Ic-1, 1.1 L of acetone was added, and 318.00 g of sodium carbonate was added. 447.11 g of methyl iodide was added dropwise to the system at 0 - 5 °C, and then the temperature was raised to room temperature for reaction. After the reaction was completed, filtration and concentration were carried out. Ethyl acetate and purified water were added to the residue and stirred until completely dissolved, and then liquid separation was carried out. The organic phase was washed with purified water and concentrated to obtain compound Id-1, which is a yellowish-brown oily substance, 227.47 g, with a yield of 102%. Compound Id-1 is a pale yellow oily substance.

[0065] (4) Preparation of compound I:

[0066] Directly take 50.0 g of compound Id-1 obtained in step (3), add 1500 ml of anhydrous tetrahydrofuran thereto, and cool to -15 - -5 °C. Replace with nitrogen and maintain a nitrogen atmosphere. 80 ml of methylmagnesium chloride solution (3 M in THF) was added dropwise to the system. After the addition, continue to keep the temperature for reaction. Carbon dioxide was introduced into the system, and then the system was slowly raised to room temperature. After the reaction was completed, ice water was added dropwise to the system. The reaction solution was concentrated. Ethyl acetate and 5 wt.% sodium hydroxide aqueous solution were added to the residue. The aqueous phase was adjusted to pH ≤ 2 with hydrochloric acid. When a solid precipitated, filtration was carried out, and drying was carried out to obtain compound I, which is a white powdery solid, 34.58 g, with a yield of 83.54%, HPLC purity ≥ 99.0%, maximum single impurity ≤ 0.2%, [M - H] + = 187.02, 1 1H-NMR (DMSO-d6, 400 Hz): 3.9(s, 3H), 7.23 - 7.29(m, H), 7.62 - 7.67(m, H), 13.41(s, H).

[0067] Example 2

[0068] This example discloses a preparation method of compound I, and the process route is as follows:

[0069]

[0070] ; The specific steps are:

[0071] (1) Preparation of compound Ib-1:

[0072] To 258.22 g of compound Ia was added 1.25 L of sulfuric acid, and 544.00 g of bromine was added at 20-30° C. The reaction was continued with stirring. After completion of the reaction, the system was poured into 25.0 L of ice water. A large amount of reddish-brown solid precipitated in the system, which was filtered and the filter cake was dried to obtain 377.10 g of compound Ib-1. The structure of the obtained compound Ib-1 was identified to be consistent with that of Ib-1 in step (1) of Example 1, with a yield of 90.65%.

[0073] (2) Preparation of compound Ic-1:

[0074] To 208.00 g of compound Ib-1 was added 1.0 L of a 5 wt.% aqueous sulfuric acid solution. 800 mL of an aqueous solution containing 79.35 g of sodium nitrite was added dropwise at 0-5° C. After completion of the reaction, the reaction mixture was added to a mixed solution containing 1 L of tetrahydrofuran and 1 L of purified water. The reaction mixture was then heated to reflux. After completion of the reaction, ethyl acetate was added to the reaction system for extraction. The organic phase was concentrated to obtain 220 g of compound Ic-1. The structure of the obtained compound Ic-1 was identified as consistent with that of Ic-1 in step (2) of Example 1, with a yield of 105.77%. Compound Ic-1 was a needle-shaped solid.

[0075] (3) Preparation of Compound Id-1:

[0076] To 220 g of compound Ic-1, 1.1 L of acetone and 318.00 g of sodium carbonate were added, followed by the dropwise addition of 258.50 g of dimethyl sulfate. The temperature was raised to reflux for reaction. After completion of the reaction, the system was cooled to room temperature, filtered, and concentrated. Ethyl acetate and a 10 wt.% aqueous sodium hydroxide solution were added to the residue and stirred to completely hydrolyze the excess dimethyl sulfate. The organic phase was washed with purified water and concentrated to obtain 256.45 g of compound Id-1 as a yellowish-brown oil with a yield of 115%. Compound Id-1 was a light yellow oil.

[0077] (4) Preparation of Compound I:

[0078] Take 50.0 g of the compound Id-1 obtained in step (3) directly, add 1500 ml of anhydrous tetrahydrofuran thereto, cool down to -15 to -5 °C, displace with nitrogen and maintain a nitrogen atmosphere, and dropwise add 290 ml of isopropylmagnesium chloride solution (1 M in THF) to the system. After the dropping is completed, continue to keep the temperature for reaction. Introduce carbon dioxide into the system, then slowly raise the temperature of the system to room temperature. After the reaction is completed, dropwise add ice water to the system, concentrate the reaction solution, add ethyl acetate and 5 wt.% sodium hydroxide aqueous solution to the residue, adjust the pH of the aqueous phase to ≤2 with hydrochloric acid to precipitate solids, filter by suction, and dry to obtain compound I. The structure of the obtained compound I was identified to be consistent with that of I in step (4) of Example 1. It is a white powdery solid of 36.29 g, with a yield of 87.62%, HPLC purity ≥99.0%, and the maximum single impurity ≤0.2%.

[0079] Example 3

[0080] This example discloses a preparation method of compound I, and the process route is as follows:

[0081]

[0082] ; The specific steps are as follows:

[0083] (1) Preparation of compound Ib-2:

[0084] Add 1.08 L of sulfuric acid to 135.56 g of compound Ia, add 252.37 g of N-chlorosuccinimide at 20 - 30 °C. After the addition is completed, raise the temperature of the system to 40 - 60 °C and stir for reaction. After the reaction is completed, pour the system into 16.2 L of ice water. Wait until a large amount of yellow solid precipitates, filter by suction, and dry to obtain 146.21 g of compound Ib-2, with a yield of 85.14%, [M+H] + = 164.01.

[0085] (2) Preparation of compound Ic-2:

[0086] Add 1.0 L of 5 wt.% sulfuric acid aqueous solution to 163.55 g of compound Ib-2, dropwise add 800 ml of an aqueous solution containing 89.70 g of sodium nitrite at 0 - 5 °C. After the dropping is completed, keep the temperature for reaction. After the reaction is completed, add the system to a mixed solution containing 1.2 L of 2-methyltetrahydrofuran and 1.8 L of purified water, then raise the temperature of the system to reflux for reaction. After the reaction is completed, add ethyl acetate to the reaction system. The organic phase is concentrated and dried to obtain 185 g of compound Ic-2, with a yield of 112%. Compound Ic-2 is a needle-like solid, with a slight sublimation phenomenon during storage at room temperature, and has an obvious odor of phenolic compounds, [M+H] + = 164.99.

[0087] (3) Preparation of Compound Id-2:

[0088] Add 0.9 L of acetone to 185 g of Compound Ic-2, then add 318.00 g of sodium carbonate, and then dropwise add 176.21 g of dimethyl sulfate. Heat up to reflux for reaction. After the reaction is completed, cool the system to room temperature, filter, and concentrate. Add ethyl acetate and 10 wt.% aqueous sodium hydroxide solution to the residue to completely hydrolyze the excess dimethyl sulfate. Wash the organic phase with purified water, concentrate to obtain Compound Id-2, which is 186.10 g of a yellow oil, with a yield of 104.22%. Compound Id-2 is a pale yellow oil.

[0089] (4) Preparation of Compound I:

[0090] Directly take 186.10 g of Compound Id-2 obtained in step (3), add 6 L of anhydrous tetrahydrofuran thereto, and cool to -40 to -20 °C. Replace with nitrogen and maintain a nitrogen atmosphere. Dropwise add 575 ml of isopropylmagnesium chloride solution (2 M in THF) to the system. After the dropwise addition, continue to keep the temperature for reaction. Pass carbon dioxide into the system, then slowly raise the system to room temperature, and continue to stir for reaction. After the reaction is completed, dropwise add ice water to the system, concentrate the reaction solution, add ethyl acetate and 5 wt.% aqueous sodium hydroxide solution to the residue, separate the organic phase, adjust the pH of the aqueous phase to ≤2 with hydrochloric acid, precipitate a solid, filter by suction, and dry to obtain Compound I. The structure of the obtained Compound I is identified to be the same as that of I in step (4) of Example 1, which is 155.30 g of a white powdery solid, with a yield of 82.55%, HPLC purity ≥99.0%, and the maximum single impurity ≤0.2%.

[0091] The embodiments described above are some embodiments of the present invention, rather than all embodiments. The detailed description of the embodiments of the present invention is not intended to limit the scope of the claimed invention, but merely represents selected embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments in the present invention without making creative efforts fall within the scope of protection of the present invention.

Claims

1. A method for preparing 2,4-difluoro-3-methoxybenzoic acid, characterized in that: The steps include: S1. Compound Ia undergoes halogenation reaction to generate compound Ib, S2. Compound Ib is diazotized and then hydrolyzed to obtain compound Ic, S3. Compound Ic undergoes methylation reaction to generate compound Id, S4. Compound Id reacts with a Grignard reagent to form compound I; Its synthetic route is as follows:

2. The method for preparing 2,4-difluoro-3-methoxybenzoic acid according to claim 1, wherein In step S1, compound Ia reacts with a halogenating agent under sulfuric acid conditions to generate compound Ib.

3. The method for preparing 2,4-difluoro-3-methoxybenzoic acid according to claim 2, wherein: The halogenating agent includes at least one of N-bromosuccinimide, bromine or N-chlorosuccinimide.

4. The method for preparing 2,4-difluoro-3-methoxybenzoic acid according to claim 1, wherein In step S2, compound Ib reacts with nitrite to form a diazonium salt, which is then hydrolyzed to form compound Ic.

5. The method for preparing 2,4-difluoro-3-methoxybenzoic acid according to claim 4, wherein: In step S2, the nitrite includes at least one of sodium nitrite and potassium nitrite; Preferably, compound Ib is reacted with nitrite under acidic conditions, more preferably in aqueous sulfuric acid; Preferably, after the reaction of the diazonium salt is completed, the system is added to a mixed solution of a first organic solvent and water, wherein the first organic solvent includes at least one of dichloromethane, tetrahydrofuran, 1,2-dichloroethane, toluene, ethyl acetate, 2-methyltetrahydrofuran, cyclopentane sulfone, cyclopentyl methyl ether, and isopropanol; in the mixed solution, the ratio of the first organic solvent to water is 1:0.5 to 1:4, preferably 1:0.5 to 1:1.

5.

6. The method for preparing 2,4-difluoro-3-methoxybenzoic acid according to claim 1, wherein In step S3, compound Ic is reacted with a methylating agent under alkaline conditions to generate compound Id.

7. The method for preparing 2,4-difluoro-3-methoxybenzoic acid according to claim 1, wherein: In step S3, the methylating agent includes at least one of methyl iodide and dimethyl sulfate; Preferably, the alkaline substance includes at least one of sodium carbonate, potassium carbonate, magnesium hydroxide, aluminum hydroxide, zinc hydroxide, copper hydroxide, ammonia water, sodium bicarbonate, potassium bicarbonate, sodium acetate, potassium acetate, and cesium carbonate.

8. The method for preparing 2,4-difluoro-3-methoxybenzoic acid according to claim 1, wherein In step S4, the Grignard reagent includes a C1-C4 magnesium halide reagent, wherein the halogen includes chlorine or bromine; preferably includes at least one of methylmagnesium chloride and isopropylmagnesium chloride.

9. The method for preparing 2,4-difluoro-3-methoxybenzoic acid according to claim 8, wherein: In step S4, compound Id is first reacted with a Grignard reagent, and then carbon dioxide is introduced.

10. The method for preparing 2,4-difluoro-3-methoxybenzoic acid according to claim 8, wherein: In step S4, the organic solvent in the Grignard reagent includes at least one of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, benzene, and acetonitrile.

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