Synthesis method of nerofloxacin intermediate 2, 4-difluoro-3-methoxy-1-benzoic acid

Abstract

The invention relates to a preparation method of a nerofloxacin intermediate 2, 4-difluoro-3-methoxy-1-benzoic acid. The invention further relates to a preparation method of the nerofloxacin intermediate 2, 4-difluoro-3-methoxy-1-benzoic acid. Specifically, the invention discloses a preparation method for preparing 2, 4-difluoro-3-methoxy-1-benzoic acid in the presence of a non-nucleophilic strong alkali reagent, the 2, 4-difluoro-3-methoxy-1-benzoic acid reacts with methyl peroxide in the presence of a non-nucleophilic strong alkali reagent, a methoxy substitution reaction is directly carried out, and then the 2, 4-difluoro-3-methoxy-1-benzoic acid is prepared in the presence of magnesium metal and carbon dioxide. Reaction conditions are mild, and industrial production is very easy.

Description

Technical Field

[0001] The invention belongs to the field of preparation of pharmaceutical intermediates, and specifically relates to a method for synthesizing nemofloxacin intermediate 2,4-difluoro-3-methoxy-1-benzoic acid. Background Art

[0002] Fluoroquinolone antibiotics (such as levofloxacin, moxifloxacin, etc.) have the characteristics of broad antibacterial spectrum, strong antibacterial activity, low adverse reactions, good tissue permeability, high oral bioavailability, long dosing interval, and convenient administration. They have been used as common antibacterial drugs in the past few decades. However, in recent years, due to the widespread and irrational use of fluoroquinolone antibiotics, the drug resistance of bacteria (especially Streptococcus pneumoniae and Haemophilus influenzae) has continued to increase, resulting in poor clinical performance in their treatment. In order to overcome the above shortcomings of fluoroquinolone antibiotics and better cope with the challenge of increasing antibacterial resistance in the process of bacterial diseases, a non-fluoroquinolone antibiotic, nemofloxacin, has attracted widespread attention. Nemofloxacin has a broad spectrum of biological activity against Gram-negative bacteria, Gram-positive bacteria, and atypical pathogens. It is also very effective against penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant pathogens.

[0003] At present, there are few reports on the industrial synthesis of nemofloxacin. Zhejiang Zhongxin Fluoromaterial Co., Ltd. has improved the synthesis route of quinolone parent fragment II (CN201210465323.9), using m-difluorobenzene as a raw material to react with an organic lithium reagent to obtain an aryl lithium intermediate, which is then reacted with a boric acid ester and quenched to obtain 2,6-difluorophenylboric acid and 2,6-difluorophenylboric acid ester, which are further oxidized and methylated to obtain 2,6-difluoroanisole, and then 2,6-difluoroanisole is reacted in the presence of an organic lithium reagent and carbon dioxide to obtain 2,4-difluoro-3-methoxybenzoic acid (I), and then acylation, cyclization, hydrolysis and other industrially mature methods are used to obtain the quinolone parent fragment (II). Many steps in this route require the use of n-butyl lithium reagents and harsh reaction conditions of -78°C. These defects are still one of the key factors restricting its industrialization.

[0004]

[0005] Therefore, there is an urgent need in the art to develop a method for preparing 2,4-difluoro-3-methoxy-1-benzoic acid with cheap raw materials, simple operation, mild reaction conditions, and easy industrial production. Summary of the invention

[0006] The purpose of the present invention is to provide a method for preparing 2,4-difluoro-3-methoxy-1-benzoic acid with greater cost advantage, simple operation, mild reaction conditions, high yield and good purity.

[0007] The first aspect of the present invention provides a method for preparing 2,4-difluoro-3-methoxy-1-benzoic acid, the method comprising the following steps:

[0008] (a) in an inert solvent, in the presence of a non-nucleophilic strong base reagent, the compound of formula II reacts with methyl peroxide to directly prepare the compound of formula III;

[0009] (b) in an inert solvent, in the presence of magnesium metal and carbon dioxide, the compound of formula III undergoes a Grignard reaction to prepare a compound of formula I;

[0010]

[0011] Wherein, X is selected from the following group: Cl, Br, I; preferably Br.

[0012] In another preferred embodiment, the non-nucleophilic strong base reagent is selected from the following group: 2,2,6,6-tetramethylpiperidinium lithium, diisopropylamide lithium, hexamethyldisilazide lithium, or a combination thereof.

[0013] In another preferred embodiment, the methyl peroxide is selected from the group consisting of tert-butyl peroxymethyl ether, methyl peroxybenzoate, di-tert-butyl peroxide, tert-butyl peroxyethyl ether, or a combination thereof.

[0014] In another preferred embodiment, the inert solvent in step (a) is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, n-hexane, toluene, or a combination thereof.

[0015] In another preferred embodiment, the amount of the inert solvent in step (a) is 3 to 15 times the mass of the compound of formula II, preferably 5 times.

[0016] In another preferred embodiment, the molar ratio of the non-nucleophilic strong base reagent to the compound of formula II is 1:1 to 2:1, preferably 1.2:1.

[0017] In another preferred embodiment, the molar ratio of the methoxy peroxide to the compound of formula II is 1:1 to 3:1, preferably 1.5:1.

[0018] In another preferred embodiment, the step (a) is carried out at low temperature;

[0019] In another preferred embodiment, the low temperature is -100 to -20°C, preferably -40 to -30°C.

[0020] In another preferred embodiment, the reaction temperature in step (b) is -20 to 70°C.

[0021] In another preferred embodiment, the reaction temperature in step (b) is 10-15°C.

[0022] In another preferred embodiment, the molar ratio of the magnesium metal to the compound of formula III is 1:1 to 3:1, preferably 1.5:1.

[0023] In another preferred embodiment, the inert solvent in step (b) is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, or a combination thereof.

[0024] In another preferred embodiment, the amount of the inert solvent in step (b) is 3 to 20 times the mass of the compound of formula III, preferably 10 times.

[0025] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The H spectrum of 2,4-difluoro-1-bromobenzene is shown.

[0027] Figure 2 The C spectrum of 2,4-difluoro-1-bromobenzene is shown.

[0028] Figure 3 The DEPT spectrum of 2,4-difluoro-1-bromobenzene is shown.

[0029] Figure 4 The F spectrum of 2,4-difluoro-1-bromobenzene is shown.

[0030] Figure 5 The mass spectrum (GC-MS) of 2,4-difluoro-1-bromobenzene is shown.

[0031] Figure 6 The H spectrum of 2,4-difluoro-3-methoxy-1-bromobenzene is shown.

[0032] Figure 7 The C spectrum of 2,4-difluoro-3-methoxy-1-bromobenzene is shown.

[0033] Figure 8 The DEPT spectrum of 2,4-difluoro-3-methoxy-1-bromobenzene is shown.

[0034] Fig. 9 The F spectrum of 2,4-difluoro-3-methoxy-1-bromobenzene is shown.

[0035] Fig.10 The mass spectrum (GC-MS) of 2,4-difluoro-3-methoxy-1-bromobenzene is shown.

[0036] Fig.11 The H spectrum of 2,4-difluoro-3-methoxy-1-benzoic acid is shown.

[0037] Fig.12 The C spectrum of 2,4-difluoro-3-methoxy-1-benzoic acid is shown.

[0038] Fig.13 The DEPT spectrum of 2,4-difluoro-3-methoxy-1-benzoic acid is shown.

[0039] Fig.14 The liquid phase purity spectrum of 2,4-difluoro-3-methoxy-1-benzoic acid in Example 1 is shown. DETAILED DESCRIPTION

[0040] After extensive and in-depth research, the inventor unexpectedly found that in an inert solvent, in the presence of a non-nucleophilic strong base reagent, the compound of formula II can be directly reacted with methyl peroxide to obtain the compound of formula III, thereby preparing the compound of formula I. The present invention shortens the lengthy reaction to two steps, is simple to operate, has mild reaction conditions, and has a high product yield and good purity. On this basis, the inventor completed the present invention.

[0041] the term

[0042] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0043] As used herein, the terms "comprise", "include", and "contain" are used interchangeably and include not only closed definitions, but also semi-closed and open definitions. In other words, the terms include "consisting of", "consisting essentially of".

[0044] The "inert solvent" described in the present invention refers to a solvent that does not react with the compounds in the reaction system.

[0045] As used herein, the terms "the method of the present invention", "the preparation method of the present invention" and "the industrial preparation method of the present invention" may be used interchangeably to refer to the method described in the first aspect of the present invention.

[0046] Compounds and preparation methods

[0047] The compound of formula I described in the present invention, "2,4-difluoro-3-methoxy-1-benzoic acid", is one of the important intermediates for preparing nemofloxacin, and its structural formula is as follows:

[0048]

[0049] The preparation method of the compound of formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combination can be easily carried out by a technician in the field to which the present invention belongs.

[0050] Typically, the preparation method of the compound of formula I of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.

[0051] The present invention provides a method for preparing 2,4-difluoro-3-methoxy-1-benzoic acid, and the specific steps are as follows:

[0052]

[0053] (i) In an inert solvent, 2,4-difluorobromobenzene is used as a raw material, and reacts with an organic lithium reagent at low temperature under the protection of an inert gas to obtain a corresponding aryl lithium intermediate;

[0054] (ii) reacting the obtained aryl lithium intermediate with a methoxy reagent in an inert solvent at low temperature, and quenching to obtain 2,4-difluoro-3-methoxy-1-bromobenzene;

[0055] (iii) In an inert solvent, 2,4-difluoro-3-methoxy-1-bromobenzene is used as a raw material, and under the protection of an inert gas, it is reacted with magnesium to prepare a Grignard reagent, which is then reacted with carbon dioxide to obtain 2,4-difluoro-3-methoxy-1-benzoic acid.

[0056] In another preferred embodiment, after the raw materials undergo Grignard reaction in step (iii), a sufficient amount of carbon dioxide needs to be added; specifically, carbon dioxide gas is introduced until the system no longer absorbs carbon dioxide, thereby obtaining the target product 2,4-difluoro-3-methoxy-1-benzoic acid.

[0057] The main advantages of the present invention are:

[0058] 1. In the present invention, under the action of methyl peroxide and a non-nucleophilic strong base reagent, 2,4-difluorobromobenzene is used as a raw material to carry out a methoxy substitution reaction at a specific site of the compound of formula II, and the reaction selectivity is high.

[0059] 2. The method of the present invention does not require the process of first hydroxyl substitution and then methoxy substitution, the route is short, the operation is simple, and multi-step dangerous reactions are avoided.

[0060] 3. The present invention provides a preparation method with high reaction yield, few impurities and good product purity.

[0061] 4. The raw materials of the present invention are easily available, the reaction is carried out under normal pressure, the conditions are relatively mild, and it is suitable for industrial production.

[0062] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0063] Unless otherwise stated, the following examples were carried out under normal pressure.

[0064] The "tert-butyl peroxymethyl ether" and "methyl peroxybenzoate" in the following examples were freshly prepared and used directly, or purchased directly.

[0065] Example 1

[0066] (1) Preparation of 2,4-difluoro-3-methoxy-1-bromobenzene

[0067] Replace the gas with nitrogen in a 500mL dry reaction bottle, add 19.3g of compound II (MW192.99, 0.1mol), 96.5g of anhydrous tetrahydrofuran, and under nitrogen protection, stir and cool the system to -40~-30℃, slowly drop 60mL (0.12mol, 1.2eq) of 2.0M lithium diisopropylamide tetrahydrofuran solution, and after the addition is complete, control the temperature at -40~-30℃ and stir to react for 2h. Keep the temperature at -40~-30℃ and slowly drop tert-butyl peroxymethyl ether (0.15mol, 1.5eq), and after the addition is complete, control the temperature at -40~-30℃ and react until the raw material is completely converted. Slowly add 100mL of water to quench the reaction, and adjust to acidity with 36% hydrochloric acid. The organic phase was extracted twice with 300 mL of ethyl acetate, and the solvent was recovered by vacuum distillation of the organic phase. The temperature was controlled at 70-80° C. and the oil pump was used for vacuum distillation to obtain 17.6 g (MW 223.02, 0.0789 mol) of the compound of formula III with a purity of 99.6% and a yield of 78.9%, which was a colorless transparent liquid.

[0068] Spectrum see Figures 1 to 10 .

[0069] (2) Preparation of 2,4-difluoro-3-methoxy-1-benzoic acid (Ⅰ)

[0070] After replacing the gas with nitrogen in a 500mL dry reaction bottle, 3g of magnesium powder (0.123mol, 1.5eq) and 175g of anhydrous tetrahydrofuran were added, and the temperature was kept at 10-15°C. 17.5g of the compound of formula III (MW223.02, 0.0785mol) was added dropwise, and the addition was completed in about 1h. The reaction was continued under nitrogen protection with stirring for 2h. The temperature was controlled at 10-15°C, and carbon dioxide gas was slowly introduced to positive pressure after vacuuming. Then 200mL of water was added to quench the reaction, and 36% hydrochloric acid was used to adjust the acidity. After heating and distilling to recover the organic solvent, the compound of formula I was filtered, washed with water, and dried to obtain 13.8g (MW188.13, 0.0734mol), with a single-step yield of 93.5%, a white solid, a purity of 99.4%, and a two-step total yield of 73.8%.

[0071] Spectrum see Figures 11 to 14 .

[0072] Example 2

[0073] The method and conditions of Example 1 were used for synthesis, except that the reaction in step (2) remained unchanged and tert-butyl peroxymethyl ether in step (1) was replaced by methyl peroxybenzoate. The total yield of the product in two steps was 72.7% and the purity was 98.5%.

[0074] Example 3

[0075] The method and conditions of Example 1 were used for the synthesis, except that the reaction in step (2) remained unchanged and the amount of tert-butyl peroxymethyl ether in step (1) was changed to 1.0 eq. The total yield of the product in two steps was 65.8% and the purity was 97.0%.

[0076] Example 4

[0077] The method and conditions of Example 1 were used for the synthesis, except that the reaction in step (2) remained unchanged and the amount of tert-butyl peroxymethyl ether in step (1) was changed to 2.0 eq. The total yield of the product in two steps was 70.5% and the purity was 96.7%.

[0078] Example 5

[0079] The method and conditions of Example 1 were used for synthesis, except that the reaction in step (2) remained unchanged and the amount of tert-butyl peroxymethyl ether in step (1) was changed to 3.0 eq. The total yield of the product in two steps was 67.1% and the purity was 95.5%.

[0080] Example 6

[0081] The method and conditions of Example 1 were used for synthesis, except that the reaction in step (2) remained unchanged and the tetrahydrofuran in step (1) was replaced by 2-methyltetrahydrofuran. The total yield of the product in two steps was 71.9% and the purity was 98.3%.

[0082] Example 7

[0083] The method and conditions of Example 1 were used for synthesis, except that the reaction in step (2) remained unchanged and tetrahydrofuran in step (1) was replaced with methyl tert-butyl ether. The total yield of the product in two steps was 72.5% and the purity was 97.0%.

[0084] Example 8

[0085] The method and conditions of Example 1 were used for synthesis, except that the reaction in step (2) remained unchanged and tetrahydrofuran in step (1) was replaced with n-hexane. The total yield of the product in two steps was 61.5% and the purity was 96.8%.

[0086] Example 9

[0087] The method and conditions of Example 1 were used for synthesis, except that the reaction in step (2) remained unchanged and only tetrahydrofuran in step (1) was replaced by toluene. The total yield of the product in two steps was 68.5% and the purity was 96.7%.

[0088] Example 10

[0089] The method and conditions of Example 1 were used for synthesis. The reaction in step (2) remained unchanged. Only the amount of tetrahydrofuran in step (1) was changed from 5 times the mass of the compound of formula II to 3 times. The total yield of the product in two steps was 73.0% and the purity was 98.3%.

[0090] Embodiment 11

[0091] The method and conditions of Example 1 were used for synthesis. The reaction in step (2) remained unchanged. Only the amount of tetrahydrofuran in step (1) was changed from 5 times the mass of the compound of formula II to 10 times. The total yield of the product in two steps was 73.3% and the purity was 99.2%.

[0092] Example 12

[0093] The method and conditions of Example 1 were used for synthesis, and the reaction of step (2) remained unchanged. Only the amount of tetrahydrofuran in step (1) was changed from 5 times the mass of the compound of formula II to 15 times. The total yield of the product in two steps was 71.5% and the purity was 98.3%.

[0094] Embodiment 13

[0095] The method and conditions of Example 1 were used for synthesis, except that the reaction temperature in step (2) was changed from -40 to -30°C to -100 to -90°C. The total yield of the product in two steps was 98.6% and the purity was 98.7%.

[0096] Embodiment 14

[0097] The method and conditions of Example 1 were used for synthesis, except that the reaction temperature in step (2) was changed from -40 to -30°C in step (1) to -60 to -50°C. The total yield of the product in two steps was 73.5% and the purity was 99.2%.

[0098] Embodiment 15

[0099] The method and conditions of Example 1 were used for synthesis, except that the reaction temperature in step (2) was changed from -40 to -30°C in step (1) to -30 to -20°C. The total yield of the product in two steps was 75.8% and the purity was 95.7%.

[0100] Example 16

[0101] The method and conditions of Example 1 were used for synthesis, except that the reaction in step (2) remained unchanged and the lithium reagent lithium diisopropylamide (LDA) in step (1) was replaced with 2,2,6,6-tetramethylpiperidinium lithium. The total yield of the product in two steps was 72.8% and the purity was 93.3%.

[0102] Embodiment 17

[0103] The method and conditions of Example 1 were used for synthesis, except that the reaction of step (2) remained unchanged and the lithium reagent lithium diisopropylamide (LDA) in step (1) was replaced with lithium hexamethyldisilazide. The total yield of the product in two steps was 69.8% and the purity was 92.0%.

[0104] Embodiment 18

[0105] The method and conditions of Example 1 were used for synthesis, except that the reaction in step (2) remained unchanged, and the amount of lithium diisopropylamide (LDA) in step (1) was changed from 1.2 eq to 1.0 eq. The total yield of the product in two steps was 61.8% and the purity was 96.8%.

[0106] Embodiment 19

[0107] The method and conditions of Example 1 were used for synthesis, except that the reaction in step (2) remained unchanged, and the amount of lithium diisopropylamide (LDA) in step (1) was changed from 1.2 eq to 1.5 eq. The total yield of the product in two steps was 66.1% and the purity was 97.2%.

[0108] Embodiment 20

[0109] The method and conditions of Example 1 were used for synthesis, except that the reaction in step (2) remained unchanged, and the amount of lithium diisopropylamide (LDA) in step (1) was changed from 1.2 eq to 2.0 eq. The total yield of the product in two steps was 62.1% and the purity was 95.3%.

[0110] Embodiment 21

[0111] The method and conditions of Example 1 were used for synthesis, except that the reaction in step (1) remained unchanged and the tetrahydrofuran in step (2) was replaced by 2-methyltetrahydrofuran. The total yield of the product in two steps was 71.1% and the purity was 99.0%.

[0112] Embodiment 22

[0113] The method and conditions of Example 1 were used for synthesis, except that the reaction in step (1) remained unchanged and tetrahydrofuran in step (2) was replaced by ether. The total yield of the product in two steps was 72.2% and the purity was 98.6%.

[0114] Embodiment 23

[0115] The method and conditions of Example 1 were used for synthesis, except that the reaction in step (1) remained unchanged and the amount of tetrahydrofuran in step (2) was changed from 10 times the mass of the compound of formula III to 3 times. The total yield of the product in two steps was 70.7% and the purity was 93.5%.

[0116] Embodiment 24

[0117] The method and conditions of Example 1 were used for synthesis, except that the reaction in step (1) remained unchanged and the amount of tetrahydrofuran in step (2) was changed from 10 times the mass of the compound of formula III to 5 times. The total yield of the product in two steps was 72.0% and the purity was 97.3%.

[0118] Embodiment 25

[0119] The method and conditions of Example 1 were used for synthesis, except that the reaction in step (1) remained unchanged and the amount of tetrahydrofuran in step (2) was changed from 10 times the mass of the compound of formula III to 20 times. The total yield of the product in two steps was 70.2% and the purity was 98.5%.

[0120] Embodiment 26

[0121] The method and conditions of Example 1 were used for synthesis, except that the reaction temperature in step (1) was changed from 10 to 15°C to -20 to -10°C. The total yield of the product in two steps was 60.3% and the purity was 98.2%.

[0122] Embodiment 27

[0123] The method and conditions of Example 1 were used for synthesis, except that the reaction temperature in step (1) was changed from 10 to 15°C to 0 to 10°C. The total yield of the product in two steps was 65.7% and the purity was 99.0%.

[0124] Embodiment 28

[0125] The method and conditions of Example 1 were used for synthesis, except that the reaction in step (1) remained unchanged and the reaction temperature in step (2) was changed from 10 to 15°C to 20 to 30°C. The total yield of the product in two steps was 66.8% and the purity was 98.5%.

[0126] Embodiment 29

[0127] The method and conditions of Example 1 were used for synthesis, except that the reaction temperature in step (1) was changed from 10 to 15°C to 60 to 70°C. The total yield of the product in two steps was 51.5% and the purity was 92.8%.

[0128] Embodiment 30

[0129] The method and conditions of Example 1 were used for synthesis, except that the reaction in step (1) remained unchanged and the amount of magnesium in step (2) was changed from 1.5 eq to 1.0 eq. The total yield of the product in two steps was 60.5% and the purity was 97.8%.

[0130] Embodiment 31

[0131] The method and conditions of Example 1 were used for the synthesis, except that the reaction in step (1) remained unchanged and the amount of magnesium in step (2) was changed from 1.5 eq to 2.0 eq. The total yield of the product in two steps was 71.5% and the purity was 99.2%.

[0132] Embodiment 32

[0133] The method and conditions of Example 1 were used for the synthesis, except that the reaction in step (1) remained unchanged and the amount of magnesium in step (2) was changed from 1.5 eq to 3.0 eq. The total yield of the product in two steps was 70.1% and the purity was 99.0%.

[0134] Embodiment 33:

[0135] The method and conditions of Example 1 were used to synthesize the product. The reaction of step (2) remained unchanged. Only the tert-butyl peroxymethyl ether in step (1) was replaced by di-tert-butyl peroxide. The total yield of 2,4-difluoro-3-tert-butoxy-1-benzoic acid in two steps was 65.7% and the purity was 96.9%.

[0136] Embodiment 34:

[0137] The method and conditions of Example 1 were used to synthesize the product. The reaction of step (2) remained unchanged. Only tert-butyl peroxymethyl ether in step (1) was replaced by tert-butyl peroxyethyl ether. The total yield of 2,4-difluoro-3-ethoxy-1-benzoic acid in two steps was 68.5% and the purity was 98.1%.

[0138] Embodiment 35:

[0139] The method and conditions of Example 1 were used for synthesis, except that the reaction in step (2) remained unchanged and 2,4-difluorobromobenzene in step (1) was replaced with 2,4-difluorochlorobenzene. The total yield of the product in two steps was 63.8% and the purity was 98.8%.

[0140] Embodiment 36:

[0141] The method and conditions of Example 1 were used for synthesis, except that the reaction in step (2) remained unchanged and 2,4-difluorobromobenzene in step (1) was replaced with 2,4-difluoroiodobenzene. The total yield of the product in two steps was 67.8% and the purity was 97.9%.

[0142] Comparative Example 1

[0143] The preparation method refers to patent CN 1284939A.

[0144] 1) Dissolve 40.2 ml of 2.0 M lithium diisopropylamine (LDA) in 80 ml of THF at -78°C, add 15.4 g of 2,4-difluorobromobenzene (MW 192.99, 0.0798 mol), keep the temperature below -65°C and stir for 2 hours, add 6.6 ml of 6 M anhydrous tert-butyl hydroperoxide. After warming to room temperature, add 100 ml of water and acidify the mixture. Evaporate the solvent, extract the water layer with ether, dry and concentrate the extract to obtain 11.83 g of 3-hydroxy-2,4-difluorobromobenzene (MV 207.93, 0.0569 mol), with a yield of 71.3%.

[0145] 2) Dissolve 3.7 g of 3-hydroxy-2,4-difluorobromobenzene (MV 207.93, 0.0178 mol) in 25 ml of acetone, add 2.5 g of potassium carbonate, and then add 2.2 ml of methyl iodide. Stir the mixture at 20°C for 6 hours and evaporate the solvent. After adding dichloromethane, filter the suspension. Evaporate the solvent to obtain 2.98 g of 3-methoxy-2,4-difluorobromobenzene (MW 223.02, 0.0134 mol), with a yield of 75.1%.

[0146] 3) At -78°C, 22 ml of ether was added to 2.15 g (MW 223.02, 0.00964 mol) of 3-methoxy-2,4-difluorobromobenzene, and 5.9 ml of 1.6 M n-butyl lithium was added to the 3-methoxy-2,4-difluorobromobenzene phase under dilution with 6 ml of ether, and the temperature was kept below -70°C. After 15 minutes, CO2 was introduced into the reaction solution, and the temperature was kept below -70°C. After warming to room temperature, water and hydrochloric acid were added, and the organic phase was separated and dried. The solvent was removed to obtain 1.61 g of compound (I) (MW 188.13, 0.00856 mol), with a yield of 88.8%, a total yield of 47.5% in three steps, and a purity of 97.1%.

[0147] Comparative Example 2

[0148] The preparation method refers to patent CN 103819401B.

[0149] 1) In a 500mL dry reaction bottle, after replacing the gas with nitrogen, add 22.8g (MV114.09, 0.20moL) m-difluorobenzene and 150mL anhydrous ether. Under nitrogen protection, the system is stirred and cooled to -90°C, and 187mL of 165M n-butyl lithium in n-pentane solution is slowly added dropwise. After the addition is complete, the temperature is controlled at -60 to -70°C and stirred for 2 hours. The system is cooled to -78°C again, 60g of trimethyl borate is added dropwise, and after the addition is complete, the temperature is controlled at -50 to -60°C and stirred for 2 hours. The reaction system is warmed to room temperature, 200mL of water is added to quench the reaction, 36% hydrochloric acid is used to adjust to acidity, the temperature is increased to distill and recover the solvent, and the temperature is controlled at 70 to 80°C and stirred for 6 hours. The system was cooled and crystallized, filtered and washed with water to obtain 27.0 g (MV157.91, 0.171 moL) (2,4-difluorophenyl) boronic acid with a yield of 85.6%.

[0150] 2) Add 31.6g (MV157.91, 0.20moL) (2,4-difluorophenyl) boronic acid, 150mL ethanol, 100mL water and 30mL acetic acid to a 500mL reaction bottle, stir at room temperature, add 34g 30% hydrogen peroxide, and stir and react at 20°C for 30 hours after the addition is complete. After the system cools to room temperature, add 200mL 10% sodium bisulfite solution, and stir for 1 hour after the addition is complete. Recover ethanol by vacuum distillation, extract the residue with ethyl acetate 3 times, each time with 100mL, combine the organic phases, dry and concentrate to obtain 23.9g (MV207.93, 0.115mol) 3-hydroxy-2,4-difluorobromobenzene, with a yield of 57.0%.

[0151] 3) Add 26.2 g (MV130.09, 0.201 moL) of 2,6-difluorophenol, 200 mL of tetrahydrofuran, and 83 g of potassium carbonate into a 500 mL reaction bottle, stir at room temperature, and dropwise add 38 g of dimethyl sulfate. After the addition is complete, continue stirring and react for 10 hours, filter, concentrate the filtrate under reduced pressure, recover the solvent, and distill the residue to obtain 26.8 g (MV144.12, 0.186 moL) of 2,6-difluoroanisole with a yield of 92.6%.

[0152] 4) Replace the gas with nitrogen in a 250mL dry reaction bottle, add 13.1g of diisopropylamine and 71.3g of tetrahydrofuran, and under the protection of nitrogen, stir and cool the system to -78°C. Slowly drop 100mL of 1.3M tert-butyl lithium in n-pentane solution. After the addition is complete, control the temperature at -40°C to 50°C and stir for 1 hour to obtain lithium diisopropylamide (LDA) solution, which is kept warm for use. Replace the gas with nitrogen in a 500mL dry reaction bottle, add 13.4g of 2,4-difluoro-3-methoxybenzene (MV144.12, 0.093mol) and 71.2g of tetrahydrofuran, and under the protection of nitrogen, stir and cool to -78°C. Slowly drop the above LDA solution. After the addition is complete, control the temperature at -50°C to 60°C and stir for 2 hours. The reaction system was cooled to -90°C, carbon dioxide was introduced, and then the temperature was slowly raised to -30°C to 40°C and stirred for 3 hours. The reaction system was warmed to room temperature, 100 mL of water was added, stirred, the aqueous phase was separated, 100 mL of ethyl acetate was added, and the mixture was adjusted to acidity with 36% hydrochloric acid, the ethyl acetate phase was separated, the aqueous phase was extracted with ethyl acetate twice, each time with 10 mL, the ethyl acetate phases were combined, dried, and concentrated to obtain compound (I) 15.1 (MW 188.13, 0.08 mol), with a yield of 86.0%, and a total yield of 38.9% in four steps. The purity was 95.7%.

[0153] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for preparing 2,4-difluoro-3-methoxy-1-benzoic acid, the method comprising the following steps: (a) in an inert solvent, in the presence of a non-nucleophilic strong base reagent, the compound of formula II reacts with methyl peroxide to directly prepare the compound of formula III; (b) in an inert solvent, in the presence of magnesium metal and carbon dioxide, the compound of formula III undergoes a Grignard reaction to prepare a compound of formula I; Wherein, X is selected from the following group: Cl, Br, I.

2. The preparation method according to claim 1, characterized in that The non-nucleophilic strong base reagent is selected from the following group: 2,2,6,6-tetramethylpiperidinium lithium, diisopropylamide lithium, hexamethyldisilazide lithium, or a combination thereof.

3. The preparation method according to claim 1, characterized in that: The methyl peroxide is selected from the group consisting of tert-butyl peroxymethyl ether, methyl peroxybenzoate, di-tert-butyl peroxide, tert-butyl peroxyethyl ether, or a combination thereof.

4. The preparation method according to claim 1, characterized in that: The inert solvent in step (a) is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, n-hexane, toluene, or a combination thereof.

5. The preparation method according to claim 1, characterized in that: The molar ratio of the non-nucleophilic strong base reagent to the compound of formula II is 1:1 to 2:1, preferably 1.2:

1.

6. The preparation method according to claim 1, characterized in that: The molar ratio of the methoxy peroxide to the compound of formula II is 1:1 to 3:1, preferably 1.5:

1.

7. The preparation method according to claim 1, characterized in that: The reaction temperature of step (a) is -100 to -20°C, preferably -40 to -30°C.

8. The preparation method according to claim 1, characterized in that: The reaction temperature in the step (b) is -20 to 70°C.

9. The preparation method according to claim 1, characterized in that: The molar ratio of the magnesium metal to the compound of formula III is 1:1 to 3:1, preferably 1.5:

1.

10. The preparation method according to claim 1, characterized in that: The inert solvent in step (b) is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, or a combination thereof.

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