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

Abstract

The invention relates to a synthesis method of a nerofloxacin malate intermediate 2, 4-difluoro-3-methoxy-1-benzoic acid. Specifically, the invention discloses a method for preparing 2, 4-difluoro-3-methoxy-1-benzoic acid by taking 2, 6-dichlorophenol as a raw material, reacting through a methylation reagent to obtain 2, 6-dichloroanisole, then carrying out fluorination reaction to obtain 2, 6-difluoroanisole, and finally preparing the 2, 4-difluoro-3-methoxy-1-benzoic acid through organic lithium and carbon dioxide. The method has the advantages of cheap raw materials, simple operation, safety, environmental protection, high yield and good purity, and is suitable for industrial production.

Description

Technical Field

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

[0002] Fluoroquinolone antibiotics (such as levofloxacin and moxifloxacin) have been widely used during the previous decades due to their broad antibacterial spectrum, strong antibacterial effect, low side effects, good tissue permeability, high oral bioavailability, and convenient administration. However, due to the excessive and improper use of such drugs in recent years, the resistance of bacteria (especially Streptococcus pneumoniae and Haemophilus influenzae) has increased, resulting in a reduction in their therapeutic effect. To solve these problems of fluoroquinolone antibiotics and better cope with the increasingly severe challenge of bacterial resistance, a new type of non-fluoroquinolone antibiotic - nemonoxacin has received extensive attention. Nemonoxacin has broad biological activities against a variety of Gram-negative bacteria, Gram-positive bacteria, and atypical pathogens, and has shown remarkable effects in combating penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant pathogenic bacteria.

[0003] Currently, the literature reports on the industrial production methods of nemonoxacin are relatively limited. Zhejiang Zhongxin Fluoride Materials Co., Ltd. has optimized the production process of quinolone parent fragment Ⅱ (patent number CN201210465323.9). Its improvements include using m-difluorobenzene as a raw material to react with an organolithium compound to generate an aryllithium intermediate. Then, this intermediate reacts with a borate ester and 2,6-difluorobenzeneboronic acid and 2,6-difluorobenzeneborate ester are obtained after the reaction is terminated. These products are transformed into 2,6-difluoroanisole through an oxidation and methylation process. Next, under the action of an organolithium reagent and carbon dioxide, 2,6-difluoroanisole is transformed into 2,4-difluoro-3-methoxybenzoic acid (Ⅰ). Subsequently, through a series of industrially mature methods, including acylation reaction, cyclization reaction, and hydrolysis reaction, the quinolone parent fragment (Ⅱ) is finally synthesized, as shown in the following figure.

[0004]

[0005] Although this route has a short synthesis step and does not require additional group protection and deprotection operations, the supply of the starting material m-difluorobenzene in the market is small, and the stable supply of raw materials is greatly restricted. At the same time, the atomic utilization rate of trimethyl borate is not high, and the oxidation with hydrogen peroxide belongs to one of the 18 types of key supervised dangerous reactions, with intense heat release and high requirements for temperature control of the reaction device. These are all factors that are not conducive to large-scale industrial production.

[0006] Therefore, there is an urgent need in the art to develop a preparation method of 2,4-difluoro-3-methoxy-1-benzoic acid that is inexpensive in raw materials, simple in operation, safe, environmentally friendly, with high yield and good purity. SUMMARY OF THE INVENTION

[0007] The purpose of the present invention is to provide a preparation method of 2,4-difluoro-3-methoxy-1-benzoic acid that is inexpensive in raw materials, simple in operation, safe, environmentally friendly, with high yield and good purity.

[0008] In the first aspect of the present invention, a preparation method of a compound of formula I is provided, and the method includes the following steps:

[0009]

[0010] (a) In an inert solvent, a compound of formula IV reacts with a methylation reagent to prepare a compound of formula III;

[0011] (b) In an inert solvent, under the action of a phase transfer catalyst, the compound of formula III undergoes a fluorination reaction with a KF reagent to prepare a compound of formula II;

[0012] (c) In an inert solvent, the compound of formula II reacts with an organolithium reagent and carbon dioxide to prepare a compound of formula I.

[0013] In another preferred example, the inert solvent in step (a) is selected from the group consisting of: tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or a combination thereof.

[0014] In another preferred example, the inert solvent in step (a) is tetrahydrofuran.

[0015] In another preferred example, the amount of the inert solvent used in step (a) is 2 to 12 times the mass of the compound of formula IV, preferably 4 times.

[0016] In another preferred example, the methylation reagent is selected from the group consisting of: dimethyl sulfate, dimethyl carbonate.

[0017] In another preferred example, the methylation reagent is dimethyl sulfate.

[0018] In another preferred example, the molar ratio of the methylation reagent to the compound of formula IV is 1:1 to 3:1, preferably 1.8:1.

[0019] In another preferred example, the inert solvent in step (b) is selected from the group consisting of: dimethyl sulfoxide, dimethylformamide, sulfolane, or a combination thereof.

[0020] In another preferred example, the inert solvent in step (b) is sulfolane.

[0021] In another preferred embodiment, the amount of the inert solvent in the step (b) is 5 to 20 times, preferably 10 times, the mass of the compound of formula III.

[0022] In another preferred embodiment, the phase transfer catalyst is selected from the group consisting of: 18-crown-6, tetrabutylammonium tetrafluoroborate, trioctylmethylammonium chloride, dibenzo-18-crown-6, benzyltriethylammonium bromide, tetraphenylphosphonium bromide, or a combination thereof.

[0023] In another preferred embodiment, the phase transfer catalyst is 18-crown-6.

[0024] In another preferred embodiment, the molar ratio of the phase transfer catalyst to the compound of formula III is 0.3:1 to 1:1, preferably 0.6:1.

[0025] In another preferred embodiment, the molar ratio of the KF reagent to the compound of formula III is 2:1 to 10:1, preferably 4:1.

[0026] In another preferred embodiment, the inert solvent in the step (c) is selected from the group consisting of: tetrahydrofuran, 2-methyltetrahydrofuran, or a combination thereof.

[0027] In another preferred embodiment, the inert solvent in the step (c) is tetrahydrofuran.

[0028] In another preferred embodiment, the amount of the inert solvent in the step (c) is 3 to 15 times, preferably 5 times, the mass of the compound of formula II.

[0029] In another preferred embodiment, the organolithium reagent is selected from the group consisting of: n-butyllithium, tert-butyllithium, lithium diisopropylamide, or a combination thereof.

[0030] In another preferred embodiment, the organolithium reagent is n-butyllithium.

[0031] In another preferred embodiment, the molar ratio of the organolithium reagent to the compound of formula II is 1:1 to 2:1, preferably 1.1:1.

[0032] In another preferred embodiment, the reaction temperature of the step (a) is 10 to 65 °C, preferably 20 to 40 °C.

[0033] In another preferred embodiment, the fluorination reaction temperature is 160 to 300 °C, preferably 220 to 240 °C.

[0034] In another preferred embodiment, the reaction temperature of the step (c) is -80 to -40 °C, preferably -70 to -60 °C.

[0035] In another preferred embodiment, the yield of the preparation method is 65% to 77%.

[0036] In a second aspect of the present invention, there is provided a method for efficiently preparing a compound of formula II, the method comprising the following steps:

[0037] (b) In an inert solvent and under the action of a phase transfer catalyst, the compound of formula III reacts with a KF reagent to undergo a fluorination reaction to prepare the compound of formula II.

[0038]

[0039] In another preferred example, the following steps are further included before step (b):

[0040] (a) In an inert solvent, the compound of formula IV reacts with a methylation reagent to prepare the compound of formula III.

[0041]

[0042] In another preferred example, the following steps are further included after step (b):

[0043] (c) In an inert solvent, the compound of formula II reacts with an organolithium reagent and carbon dioxide to prepare the compound of formula I.

[0044]

[0045] In another preferred example, there is provided a use of the step (b) for preparing 2,4-difluoro-3-methoxy-1-benzoic acid (formula I).

[0046] In another preferred example, the yield of the step (b) is 80-95%; preferably 90-95%.

[0047] 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 in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be elaborated one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 Shows the hydrogen spectrum of the product 2,4-difluoro-3-methoxy-1-benzoic acid.

[0049] Figure 2 Shows the carbon spectrum of the product 2,4-difluoro-3-methoxy-1-benzoic acid.

[0050] Figure 3 Shows the liquid phase purity spectrum of the product 2,4-difluoro-3-methoxy-1-benzoic acid. DETAILED DESCRIPTION OF THE INVENTION

[0051] After extensive and in-depth research, the present inventor has developed a brand-new method for preparing 2,4-difluoro-3-methoxy-1-benzoic acid. The method uses a compound of formula IV as a raw material to prepare a compound of formula III through a methylation reaction. Subsequently, under the action of a phase transfer catalyst, it reacts with a KF reagent to undergo a fluorination reaction to obtain a compound of formula II. Finally, after reacting with an organolithium reagent and carbon dioxide, a compound of formula I is prepared. At the same time, it was unexpectedly found that the compound of formula III and the KF reagent can be used to prepare the compound of formula II with high yield and high purity under the action of a phase transfer catalyst. This step (i.e., step b) plays an important role in the present invention. The method for preparing 2,4-difluoro-3-methoxy-1-benzoic acid according to the present invention is safe, environmentally friendly, simple to operate, inexpensive in raw materials, and has a high product yield and good purity. On this basis, the inventor has completed the present invention.

[0052] Term

[0053] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this invention belongs.

[0054] As used herein, the terms "comprising", "including", and "containing" are used interchangeably and include not only closed definitions but also semi-closed and open definitions. In other words, these terms include "consisting of" and "consisting essentially of".

[0055] The "inert solvent" as used in the present invention refers to a solvent that does not react with the compounds in the reaction system.

[0056] 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" can be used interchangeably and refer to the method described in the first aspect of the present invention.

[0057] Compound and preparation method

[0058] The compound of formula I "2,4-difluoro-3-methoxy-1-benzoic acid" as used in the present invention is one of the important intermediates for preparing nirmatrelvir, and its structural formula is as follows:

[0059]

[0060] The preparation method of the compound of formula I according to the present invention is described in more detail below, but these specific methods do not impose any limitations on the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthesis methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention belongs.

[0061] The present invention provides a method for efficiently obtaining the compound of formula I, which method has low raw material cost and safe, environmentally friendly reactions. The specific steps are as follows:

[0062]

[0063] (a) In an inert solvent, the compound of formula IV reacts with a methylation reagent to prepare the compound of formula III;

[0064] (b) In an inert solvent, under the action of a phase transfer catalyst, the compound of formula III undergoes a fluorination reaction with a KF reagent to prepare the compound of formula II;

[0065] (c) In an inert solvent, the compound of formula II reacts with an organolithium reagent and carbon dioxide to prepare the compound of formula I.

[0066] Specifically, the present invention also provides a method for efficiently preparing the compound of formula II, which method comprises the following steps:

[0067] (b) In an inert solvent, under the action of a phase transfer catalyst, the compound of formula III undergoes a fluorination reaction with a KF reagent to prepare the compound of formula II.

[0068]

[0069] Preferably, the compound of formula III can be purchased commercially or can be prepared by the following steps, which steps are added before step (b):

[0070] (a) In an inert solvent, the compound of formula IV reacts with a methylation reagent to prepare the compound of formula III.

[0071]

[0072] Preferably, after step (b), the following steps are further included:

[0073] (c) In an inert solvent, the compound of formula II reacts with an organolithium reagent and carbon dioxide to prepare the compound of formula I.

[0074]

[0075] Preferably, step (b) is used for preparing 2,4-difluoro-3-methoxy-1-benzoic acid of formula I.

[0076] Preferably, the yield of step (b) is 80-95%; preferably 90-95%.

[0077] Typically, the preparation method of the compound of formula I of the present invention is as follows. Unless otherwise specified, the raw materials and reagents used can be purchased through commercial channels.

[0078] The present invention provides a preparation method of 2,4-difluoro-3-methoxy-1-benzoic acid, which has cheap raw materials, simple operation, safety and environmental protection, high yield and good purity.

[0079]

[0080] Specifically, the preparation method includes the following steps: using 2,6-dichlorophenol as a raw material, reacting with a methylation reagent to obtain 2,6-dichloroanisole, then performing a fluorination reaction to obtain 2,6-difluoroanisole, and finally preparing 2,4-difluoro-3-methoxy-1-benzoic acid through organolithium and carbon dioxide.

[0081] In the described preparation method, the compound of formula IV and all other raw materials are simple and easily available, not affected by market supply. The route avoids the use of dangerous reactions such as hydrogen peroxide oxidation, reducing the HSE risk in large-tonnage production. At the same time, compared with the prior art, this route has higher atom economy, further reducing the production cost of the key intermediate 2,4-difluoro-3-methoxy-1-benzoic acid and improving the market competitiveness of the final product nalidixic acid.

[0082] The main advantages of the present invention are as follows:

[0083] 1. The present invention provides a method for preparing the compound of formula III from the compound of formula IV. The compound of formula IV has a large market supply and low price, reducing the production cost.

[0084] 2. The present invention provides a preparation method of 2,4-difluoro-3-methoxy-1-benzoic acid with high reaction yield, few impurities and good purity.

[0085] 3. The present invention also provides a method for preparing the compound of formula II from the compound of formula III through a KF reagent. The method has a high yield and good product purity.

[0086] 4. The preparation method of the present invention has simple operation, avoids the use of dangerous reactions, and is suitable for industrial production.

[0087] The following further elaborates the present invention in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions indicated in the following embodiments are usually carried out under conventional conditions or according to the conditions recommended by the manufacturers. Unless otherwise specified, percentages and parts are calculated by weight.

[0088] Unless otherwise specified, the following embodiments are all carried out under normal pressure.

[0089] Example 1:

[0090] (1) Preparation of 2,6-dichloroanisole (III)

[0091] Add a sodium hydroxide solution of 16.7 g (MW 161.96, 103 mmol) of compound (IV), 66.8 g of tetrahydrofuran into a 250 mL reaction flask. Control the reaction temperature at 20 - 40 °C, and dropwise add 23.3 g (185 mmol, 1.80 eq) of dimethyl sulfate. After dropping, react for 3 h. Add ethyl acetate for liquid separation. After the organic phase is recovered of the solvent, distill under reduced pressure to obtain 17.1 g (MW 175.98, 97 mmol) of compound (III), with a yield of 94.2%.

[0092] (2) Preparation of 2,6-difluoroanisole (II)

[0093] Add 22.5 g (MW 58.097, 388 mmol) of KF and 15.33 g of 18-crown-6 (MW 264.32, 58 mmol) into a dry and clean 500 mL autoclave. Add 17.0 g (MW 175.98, 97 mmol) of compound (III) and 170 g of sulfolane. Replace with nitrogen three times, and heat up to 220 - 240 °C for reaction for 8 - 16 hours. After the reaction is completed, cool down, and distill at 170 °C under normal pressure to obtain 13.14 g (MW 144.04, 91 mmol) of compound (II), with a yield of 94.5%.

[0094] (3) Preparation of 2,4-difluoro-3-methoxy-1-benzoic acid (I)

[0095] Add 13.0 g (MW 144.04, 90 mmol) of compound (II) and 65 g of tetrahydrofuran into a 250 mL three-necked flask. After evacuating and replacing with nitrogen 3 times; dropwise add 39.7 mL (99 mmol, 1.10 eq) of 2.5 M n-butyllithium at -70 - -60 °C. After dropping, continue to keep the temperature for reaction for 2 h; slowly introduce carbon dioxide at -70 - -60 °C. After introducing, continue to keep the temperature for reaction for 1 h. Add water for extraction and liquid separation, separate the organic layer, and distill off the residual organic solvent from the aqueous layer under reduced pressure. Dropwise add sulfuric acid to adjust the pH = 1 - 2, filter by suction, and vacuum dry the filter cake at 50 °C to obtain 14.71 g (MW 188.03, 78 mmol) of compound (I), with a yield of 86.7%. The total yield of the three steps is 77.2%, and the liquid phase purity is 99.4%.

[0096] The hydrogen spectrum, carbon spectrum and liquid phase purity spectrum of the compound of formula I are shown in Figures 1 to 3 .

[0097] Example 2:

[0098] Synthesized according to the method and conditions of Example 1, the reactions in steps (2) and (3) remain unchanged. Only change dimethyl sulfate in step (1) to dimethyl carbonate. The overall yield of the three-step product is 73.7%, and the purity is 98.9%.

[0099] Example 3:

[0100] Synthesized according to the method and conditions of Example 1, the reactions in steps (2) and (3) remain unchanged. Only change the dosage of dimethyl sulfate in step (1) to 1.0 eq. The overall yield of the three-step product is 65.8%, and the purity is 98.1%.

[0101] Example 4:

[0102] Synthesized according to the method and conditions of Example 1, the reactions in steps (2) and (3) remain unchanged. Only change the dosage of dimethyl sulfate in step (1) to 3.0 eq. The overall yield of the three-step product is 77.1%, and the purity is 99.5%.

[0103] Example 5:

[0104] Synthesized according to the method and conditions of Example 1, the reactions in steps (2) and (3) remain unchanged. Only change tetrahydrofuran in step (1) to 2-methyltetrahydrofuran. The overall yield of the three-step product is 75.2%, and the purity is 98.9%.

[0105] Example 6:

[0106] Synthesized according to the method and conditions of Example 1, the reactions in steps (2) and (3) remain unchanged. Only change tetrahydrofuran in step (1) to toluene. The overall yield of the three-step product is 73.1%, and the purity is 99.4%.

[0107] Example 7:

[0108] Synthesized according to the method and conditions of Example 1, the reactions in steps (2) and (3) remain unchanged. Only change the dosage of tetrahydrofuran in step (1) from 4 times the mass of 2,6-dichlorophenol to 2 times. The overall yield of the three-step product is 75.0%, and the purity is 98.7%.

[0109] Example 8:

[0110] Synthesized according to the method and conditions of Example 1, the reactions in steps (2) and (3) remain unchanged. Only change the dosage of tetrahydrofuran in step (1) from 4 times the mass of 2,6-dichlorophenol to 12 times. The overall yield of the three-step product is 77.1%, and the purity is 99.1%.

[0111] Example 9:

[0112] Synthesized according to the method and conditions of Example 1, the reactions in steps (2) and (3) remain unchanged. Only change the reaction temperature in step (1) from 20 - 40 °C to 55 - 65 °C. The overall yield of the three-step product is 68.6%, and the purity is 99.1%.

[0113] Example 10:

[0114] Synthesized according to the method and conditions of Example 1. The reactions in steps (2) and (3) remain unchanged. Only change the reaction temperature in step (1) from 20 - 40°C to 10 - 20°C. The overall yield of the three-step product is 70.3% and the purity is 98.8%.

[0115] Example 11:

[0116] Synthesized according to the method and conditions of Example 1. The reactions in steps (1) and (3) remain unchanged. Only change the solvent sulfolane in step (2) to dimethyl sulfoxide. The yield of step (2) is 85.6%. The overall yield of the three-step product is 69.6% and the purity is 98.4%.

[0117] Example 12:

[0118] Synthesized according to the method and conditions of Example 1. The reactions in steps (1) and (3) remain unchanged. Only change the solvent sulfolane in step (2) to dimethylformamide. The yield of step (2) is 80.1%. The overall yield of the three-step product is 65.2% and the purity is 99.1%.

[0119] Example 13:

[0120] Synthesized according to the method and conditions of Example 1. The reactions in steps (1) and (3) remain unchanged. Only change the amount of sulfolane in step (2) from 10 times the mass of 2,6-dichloroanisole to 20 times. The yield of step (2) is 86.2%. The overall yield of the three-step product is 70.2% and the purity is 98.7%.

[0121] Example 14:

[0122] Synthesized according to the method and conditions of Example 1. The reactions in steps (1) and (3) remain unchanged. Only change the amount of sulfolane in step (2) from 10 times the mass of 2,6-dichloroanisole to 5 times. The yield of step (2) is 91.0%. The overall yield of the three-step product is 74.5% and the purity is 98.9%.

[0123] Example 15:

[0124] Synthesized according to the method and conditions of Example 1. The reactions in steps (1) and (3) remain unchanged. Only change 18-crown-6 in step (2) to tetrabutylammonium tetrafluoroborate. The yield of step (2) is 81.1%. The overall yield of the three-step product is 66.1% and the purity is 99.2%.

[0125] Example 16:

[0126] Synthesized under the method and conditions of Example 1. The reactions in steps (1) and (3) remain unchanged. Only change 18-crown-6 in step (2) to trimethyl octyl ammonium chloride. The yield of step (2) is 84.2%, and the overall yield of the three-step product is 68.5% with a purity of 98.5%.

[0127] Example 17:

[0128] Synthesized under the method and conditions of Example 1. The reactions in steps (1) and (3) remain unchanged. Only change 18-crown-6 in step (2) to dibenzo-18-crown-6. The yield of step (2) is 86.6%, and the overall yield of the three-step product is 70.7% with a purity of 99.1%.

[0129] Example 18:

[0130] Synthesized under the method and conditions of Example 1. The reactions in steps (1) and (3) remain unchanged. Only change 18-crown-6 in step (2) to benzyltriethylammonium bromide. The yield of step (2) is 83.0%, and the overall yield of the three-step product is 67.9% with a purity of 98.9%.

[0131] Example 19:

[0132] Synthesized under the method and conditions of Example 1. The reactions in steps (1) and (3) remain unchanged. Only change 18-crown-6 in step (2) to tetraphenylphosphonium bromide. The yield of step (2) is 85.4%, and the overall yield of the three-step product is 69.6% with a purity of 99.2%.

[0133] Example 20:

[0134] Synthesized under the method and conditions of Example 1. The reactions in steps (1) and (3) remain unchanged. Only change the amount of 18-crown-6 in step (2) to 1.0 eq. The yield of step (2) is 90.3%, and the overall yield of the three-step product is 73.6% with a purity of 99.4%.

[0135] Example 21:

[0136] Synthesized under the method and conditions of Example 1. The reactions in steps (1) and (3) remain unchanged. Only change the amount of 18-crown-6 in step (2) to 0.3 eq. The yield of step (2) is 85.0%, and the overall yield of the three-step product is 69.6% with a purity of 98.9%.

[0137] Example 22:

[0138] Synthesized under the method and conditions of Example 1. The reactions in steps (1) and (3) remain unchanged. Only change the amount of KF in step (2) to 10 eq. The yield of step (2) is 93.3%, and the overall yield of the three-step product is 76.1% with a purity of 99.1%.

[0139] Example 23:

[0140] Synthesized under the method and conditions of Example 1. The reactions in steps (1) and (3) remain unchanged. Only change the dosage of KF in step (2) to 2eq. The yield of step (2) is 84.8%, and the overall yield of the three-step product is 69.3% with a purity of 98.8%.

[0141] Example 24:

[0142] Synthesized under the method and conditions of Example 1. The reactions in steps (1) and (3) remain unchanged. Only change the reaction temperature in step (2) from 220 - 240 °C to 160 - 180 °C. The yield of step (2) is 81.5%, and the overall yield of the three-step product is 66.5% with a purity of 99.1%.

[0143] Example 25:

[0144] Synthesized under the method and conditions of Example 1. The reactions in steps (1) and (3) remain unchanged. Only change the reaction temperature in step (2) from 220 - 240 °C to 280 - 300 °C. The yield of step (2) is 90.9%, and the overall yield of the three-step product is 74.1% with a purity of 98.9%.

[0145] Example 26:

[0146] Synthesized under the method and conditions of Example 1. The reactions in steps (1) and (2) remain unchanged. Only change n-butyllithium in step (3) to tert-butyllithium. The overall yield of the three-step product is 69.3% with a purity of 98.7%.

[0147] Example 27:

[0148] Synthesized under the method and conditions of Example 1. The reactions in steps (1) and (2) remain unchanged. Only change n-butyllithium in step (3) to lithium diisopropylamide. The overall yield of the three-step product is 68.8% with a purity of 99.2%.

[0149] Example 28:

[0150] Synthesized under the method and conditions of Example 1. The reactions in steps (1) and (2) remain unchanged. Only change the dosage of n-butyllithium in step (3) from 1.10eq to 1.0eq. The overall yield of the three-step product is 65.8% with a purity of 98.6%.

[0151] Example 29:

[0152] Synthesized under the method and conditions of Example 1. The reactions in steps (1) and (2) remain unchanged. Only change the dosage of n-butyllithium in step (3) from 1.10eq to 2.0eq. The overall yield of the three-step product is 72.2% with a purity of 99.3%.

[0153] Example 30:

[0154] Synthesized according to the method and conditions of Example 1. The reactions in steps (1) and (2) remain unchanged. Only in step (3), tetrahydrofuran is changed to 2-methyltetrahydrofuran. The overall yield of the three-step product is 74.1% and the purity is 99.1%.

[0155] Example 31:

[0156] Synthesized according to the method and conditions of Example 1. The reactions in steps (1) and (2) remain unchanged. Only in step (3), the amount of tetrahydrofuran which is 5 times the mass of 2,6-difluoroanisole is changed to 3 times. The overall yield of the three-step product is 71.3% and the purity is 99.3%.

[0157] Example 32:

[0158] Synthesized according to the method and conditions of Example 1. The reactions in steps (1) and (2) remain unchanged. Only in step (3), the amount of tetrahydrofuran which is 5 times that of 2,6-difluoroanisole is changed to 15 times. The overall yield of the three-step product is 75.2% and the purity is 98.9%.

[0159] Example 33:

[0160] Synthesized according to the method and conditions of Example 1. The reactions in steps (1) and (2) remain unchanged. Only in step (3), the reaction temperature of -70 to -60 °C is changed to -50 to -40 °C. The overall yield of the two-step product is 70.6% and the purity is 98.8%.

[0161] Example 34:

[0162] Synthesized according to the method and conditions of Example 1. The reactions in steps (1) and (2) remain unchanged. Only in step (3), the reaction temperature of -70 to -60 is changed to -80 to -70 °C. The overall yield of the two-step product is 72.1% and the purity is 99.8%.

[0163] Comparative Example 1

[0164] The preparation method refers to Patent CN 103819401 B

[0165] Step 1: In a 500 mL dry reaction flask, after purging the gas with nitrogen, add 22.8 g (MV 114.09, 0.20 moL) of m-difluorobenzene and 150 mL of anhydrous diethyl ether. Under nitrogen protection, the system is stirred and cooled to -90 °C, and 187 mL of a 1.65 M n-butyllithium solution in n-pentane 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 again to -78 °C, and 60 g of trimethyl borate is added dropwise. 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, 200 mL of water is added to quench the reaction, and it is adjusted to acidic with 36% hydrochloric acid. The solvent is recovered by distillation under heating, and the temperature is controlled at 70 to 80 °C and stirred for 6 hours. The system is cooled to crystallize, filtered, and washed with water to obtain 27.0 g (MV 157.91, 0.171 moL) of (2,4-difluorophenyl)boronic acid, with a yield of 85.6%.

[0166] Step 2: Add 31.6 g (MV 157.91, 0.20 moL) of (2,4-difluorophenyl)boronic acid, 150 mL of ethanol, 100 mL of water, and 30 mL of acetic acid to a 500 mL reaction flask. Stir at room temperature and add 34 g of 30% hydrogen peroxide dropwise. After the addition is complete, the temperature is controlled at 20 °C and stirred for 30 hours. After the system is cooled to room temperature, 200 mL of 10% sodium bisulfite solution is added dropwise. After the addition is complete, stir for 1 hour. Ethanol is recovered by distillation under reduced pressure, and the residue is extracted with ethyl acetate 3 times, 100 mL each time. The organic phases are combined, dried, and concentrated to obtain 23.9 g (MV 207.93, 0.115 mol) of 3-hydroxy-2,4-difluorobromobenzene, with a yield of 57.0%.

[0167] Step 3: Add 26.2 g (MV 130.09, 0.201 moL) of 2,6-difluorophenol, 200 mL of tetrahydrofuran, and 83 g of potassium carbonate to a 500 mL reaction flask. Stir at room temperature and add 38 g of dimethyl sulfate dropwise. After the addition is complete, continue to stir and react for 10 hours. Filter, and the filtrate is concentrated under reduced pressure to recover the solvent. The residue is distilled to obtain 26.8 g (MV 144.12, 0.186 moL) of 2,6-difluoroanisole, with a yield of 92.6%.

[0168] Step 4: In a 250 mL dry reaction flask, replace the gas with nitrogen, add 13.1 g of diisopropylamine and 71.3 g of tetrahydrofuran. Under the protection of nitrogen, stir and cool the system to -78 °C. Slowly add dropwise 100 mL of a 1.3 M solution of tert-butyllithium in n-pentane. After the addition is complete, control the temperature at -40 °C to 50 °C and stir for 1 hour to prepare a solution of lithium diisopropylamide (LDA), and keep it warm for later use. In a 500 mL dry reaction flask, replace the gas with nitrogen, add 13.4 g (MW 144.12, 0.093 mol) of 2,4-difluoro-3-methoxybenzene and 71.2 g of tetrahydrofuran. Under the protection of nitrogen, stir and cool the temperature to -78 °C, and slowly add dropwise the above LDA solution. After the addition is complete, control the temperature at -50 °C to 60 °C and stir for 2 hours. Cool the reaction system to -90 °C, introduce carbon dioxide, and then slowly warm up to -30 °C to 40 °C and stir for 3 hours. Let the reaction system return to room temperature, add 100 mL of water, stir, separate the aqueous phase, add 100 mL of ethyl acetate, adjust to acidic with 36% hydrochloric acid, separate the ethyl acetate phase, extract the aqueous phase with ethyl acetate twice, 10 mL each time, combine the ethyl acetate phases, dry and concentrate to obtain 15.1 g (MW 188.13, 0.08 mol) of compound (I), with a yield of 86.0%, and the total yield of four steps is 38.9%. The purity is 95.7%.

[0169] All documents mentioned in the present invention are cited in this application as references, as if each document was cited separately as a reference. 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 appended claims of this application.

Claims

1. A method for preparing a compound of formula I, comprising the following steps: (a) reacting a compound of formula IV with a methylating agent in an inert solvent to prepare a compound of formula III; (b) in an inert solvent, in the presence of a phase transfer catalyst, the compound of formula III undergoes a fluorination reaction with a KF reagent to prepare a compound of formula II; (c) In an inert solvent, the compound of formula II is reacted with an organic lithium reagent and carbon dioxide to prepare a compound of formula I.

2. The method according to claim 1, characterized in that The inert solvent in step (a) is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or a combination thereof; and / or The amount of the inert solvent used is 2 to 12 times the mass of the compound of formula IV, preferably 4 times.

3. The preparation method according to claim 1, characterized in that: The methylating agent is selected from the group consisting of dimethyl sulfate, dimethyl carbonate; and / or The molar ratio of the methylating agent to the compound of formula IV is 1:1 to 3:1, preferably 1.8:

1.

4. The method according to claim 1, characterized in that The inert solvent in step (b) is selected from the group consisting of dimethyl sulfoxide, dimethylformamide, sulfolane, or a combination thereof; and / or The amount of the inert solvent used is 5 to 20 times the mass of the compound of formula III, preferably 10 times.

5. The method according to claim 1, characterized in that The phase transfer catalyst is selected from the group consisting of octadecacrown ether-6, tetrabutylammonium tetrafluoroborate, trioctylmethylammonium chloride, dibenzooctadecacrown ether-6, benzyltriethylammonium bromide, tetraphenylphosphonium bromide, or a combination thereof; and / or The molar ratio of the phase transfer catalyst to the compound of formula III is 0.3:1 to 1:1, preferably 0.6:

1.

6. The method according to claim 1, characterized in that The molar ratio of the KF reagent to the compound of formula III is 2:1 to 10:1, preferably 4:

1.

7. The method according to claim 1, characterized in that The inert solvent in step (c) is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, or a combination thereof; and / or The amount of the inert solvent used is 3 to 15 times the mass of the compound of formula II, preferably 5 times.

8. The method according to claim 1, characterized in that The organolithium reagent is selected from the group consisting of n-butyl lithium, tert-butyl lithium, lithium diisopropylamide, or a combination thereof; and / or The molar ratio of the organolithium reagent to the compound of formula II is 1:1 to 2:1, preferably 1.1:

1.

9. The method according to claim 1, characterized in that The reaction temperature of step (a) is 10-65°C, preferably 20-40°C; and / or The fluorination reaction temperature is 160-300°C, preferably 220-240°C; and / or The reaction temperature of step (c) is -80 to -40°C, preferably -70 to -60°C.

10. The method according to claim 1, characterized in that The yield of the preparation method is 65% to 75%.

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