The invention relates to a preparation method of 3, 5-difluoro-4-amino-4apos; synthetic method of-iodobiphenyl

Abstract

The invention belongs to the technical field of synthesis of drug intermediates, and discloses a synthesis method of 3, 5-difluoro-4-amino-4 '-iodobiphenyl, which comprises the following steps: S1, mixing 4-bromo-2, 6-difluoroaniline, bis (pinacolato) diboron, alkali and a solvent, adding a catalyst, and carrying out heating reaction in an inert environment to obtain a compound 2; s2, mixing the compound 2, 1-bromo-4-trimethylsilylbenzene, alkali and a solvent, adding a catalyst, and carrying out heating and stirring reaction in an inert environment to obtain a compound 3; and S3, mixing the compound 3 with an iodine chloride solution, and carrying out a stirring reaction at a certain temperature in an inert environment to obtain a target product 3, 5-difluoro-4-amino-4 '-iodobiphenyl. According to the method, 4-bromo-2, 6-difluoroaniline is taken as a starting raw material, 3, 5-difluoro-4-amino-4 '-iodobiphenyl is synthesized through a three-step reaction, and the method has the advantages that the raw materials are easy to obtain, the reaction steps are few, the yield of a target product is high, industrial large-scale production can be carried out, and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediate synthesis, and specifically relates to a method for synthesizing 3,5-difluoro-4-amino-4'-iodobiphenyl. Background Art

[0002] Aromatic fluorides are important intermediates for the synthesis of medicines, pesticides and dyes, and are widely used in materials chemistry and polymer chemistry. Among them, 3,5-difluoro-4-amino-4′-iodobiphenyl is not only widely used in crystal materials, but also very important in the research and development of new drugs because its 4-position amino group has a highly active reaction site and can undergo amino addition reaction, amino oxidation reaction, amino condensation and amino hydrolysis reaction with some fragments or drug intermediates. 3,5-difluoro-4-amino-4′-iodobiphenyl plays an important role in the application of crystal materials and new drug research and development. However, there is no literature report on the method of synthesizing 3,5-difluoro-4-amino-4′-iodobiphenyl. Therefore, the study of synthesizing 3,5-difluoro-4-amino-4′-iodobiphenyl from simple raw materials has very important theoretical significance and industrial practical prospects. Summary of the invention

[0003] In view of the above technical problems, the present invention provides a method for synthesizing 3,5-difluoro-4-amino-4′-iodobiphenyl. The method uses 4-bromo-2,6-difluoroaniline as a starting material and synthesizes 3,5-difluoro-4-amino-4′-iodobiphenyl through a three-step reaction. The method has the advantages of easy availability of raw materials, environmental friendliness and high yield.

[0004] To achieve this object, the present invention provides a method for synthesizing 3,5-difluoro-4-amino-4′-iodobiphenyl, and the synthetic route is as follows:

[0005]

[0006] The route includes the following steps:

[0007] Step S1, after mixing 4-bromo-2,6-difluoroaniline, bipyraclostrobin, a base and a solvent, adding a catalyst, and heating the mixture under an inert environment to obtain a compound 2, wherein the compound 2 is 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline;

[0008] Step S2, compound 2, 1-bromo-4-trimethylsilylbenzene, a base and a solvent are mixed, a catalyst is added, and the mixture is heated and stirred under an inert environment to obtain compound 3 ；

[0009] Step S3, mixing compound 3 with a solution of iodine chloride, stirring and reacting in an inert environment at a certain temperature to obtain the target product, namely 3,5-difluoro-4-amino-4′-iodobiphenyl.

[0010] Preferably, in step S1, the inert environment is a nitrogen environment, the base is any one of potassium acetate, sodium carbonate, potassium carbonate or cesium carbonate, the solvent is dimethyl sulfoxide, and the catalyst is 1,1-bis(diphenylphosphine)diiron palladium dichloride or 1,1-bis(diphenylphosphine)diiron palladium dichloride dichloromethane complex.

[0011] Preferably, in step S1, the equivalent ratio of the amount of 4-bromo-2,6-difluoroaniline to the base is 1 to 2, the equivalent ratio of the amount of 4-bromo-2,6-difluoroaniline to the catalyst is 0.01 to 0.03, and the temperature is raised to 80° C. to 100° C. for reaction for 6 h to 12 h.

[0012] More preferably, in step S1, potassium acetate is used as the base, the equivalent ratio of potassium acetate to 4-bromo-2,6-difluoroaniline is 1.3, 1,1-bis(diphenylphosphine)diferropalladium dichloride is used as the catalyst, and the temperature is raised to 90° C. for reaction for 8 hours.

[0013] Preferably, the reaction solution containing the compound 2 prepared in step S1 is directly used in the reaction of step S2 without being treated.

[0014] Preferably, in step S2, the inert environment is a nitrogen environment, the base is any one of potassium acetate, sodium carbonate, potassium phosphate, cesium carbonate or potassium acetate, the solvent is dimethyl sulfoxide, and the catalyst is 1,1-bis(diphenylphosphine)diiron palladium dichloride or 1,1-bis(diphenylphosphine)diiron palladium dichloride dichloromethane complex.

[0015] Preferably, in step S2, the equivalent ratio of the amount of compound 2 to 1-bromo-4-trimethylsilylbenzene is 1:1 to 1:2; the equivalent ratio of compound 2 to the catalyst is 1:0.01 to 1:0.03, and the temperature is raised to 70°C to 100°C for reaction for 6h to 12h.

[0016] More preferably, in step S2, the base is potassium phosphate, the equivalent ratio of the amount of potassium phosphate to the amount of compound 2 is 1.5, the catalyst is 1,1-bis(diphenylphosphine)diphenylferric palladium dichloride, and the temperature is raised to 80° C. for reaction for 8 h.

[0017] Preferably, in step S3, the equivalent ratio of compound 3 to iodine chloride is 1:1 to 1:4, and the reaction temperature is 0°C to 25°C.

[0018] Preferably, the specific operation of step S3 is: adding the compound 3 and dichloromethane to the reaction container, replacing with nitrogen at room temperature, and lowering the reaction system to 0°C, slowly dropping the dichloromethane solution of iodine chloride at 0°C to 5°C, reacting at room temperature for 0.5 hours, adding sodium thiosulfate aqueous solution to quench the reaction after the reaction is completed, and then adding saturated sodium bicarbonate aqueous solution to adjust the pH of the reaction system to 8 to 9; adding water to separate and collect the organic phase, and extracting the aqueous phase with dichloromethane to obtain an organic phase, combining the organic phases obtained twice, washing with saturated sodium chloride aqueous solution, drying with anhydrous sodium sulfate, reducing the pressure to remove most of the liquid, and crystallizing with dichloromethane at -20°C to obtain a solid product, i.e., the target product compound 4. The dichloromethane solution of iodine chloride consists of 253g of iodine chloride and 1.8L of dichloromethane, and the sodium thiosulfate aqueous solution consists of 82g of sodium thiosulfate and 500ml of water.

[0019] Compared with the prior art, the present invention has at least the following beneficial effects:

[0020] 1. The raw materials are easily available, the reaction steps are few and the yield of the target product is high;

[0021] 2. It can be scaled up for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is the HPLC characterization chart of compound 2 prepared in Preparation Example 5.

[0023] Figure 2 This is the NMR spectrum of compound 3 prepared in Preparation Example 15.

[0024] Figure 3 This is the HPLC characterization chart when the reaction in Preparation Example 15 was stopped.

[0025] Figure 4 This is the HPLC characterization chart when the reaction in Example 2 was stopped.

[0026] Figure 5 This is the NMR spectrum of compound 4 prepared in Example 2. DETAILED DESCRIPTION

[0027] The technical solution of the present invention is further described below in conjunction with the accompanying drawings and through specific implementation methods. However, the following examples are only simplified examples of the present invention and do not represent or limit the scope of protection of the present invention. The scope of protection of the present invention shall be subject to the claims.

[0028] The sources of the raw materials, materials and instruments involved in the following preparation examples and embodiments are as follows:

[0029] Material Name CAS source 4-Bromo-2,6-difluoroaniline 67567-26-4 Available in the market 1-Bromo-4-trimethylsilylbenzene 6999-03-7 Available in the market Iodine monochloride 7790-99-0 Available in the market Pinacol borate 73183-34-3 Available in the market Potassium Phosphate 7778-53-2 Available in the market Potassium acetate 127-08-2 Available in the market 1,1-Bis(diphenylphosphine)ferrocenepalladium(II) chloride 72287-26-4 Available in the market Dimethyl sulfoxide 67-68-5 Available in the market Dichloromethane 75-09-2 Available in the market

[0030] instrument factory model Liquid chromatography (HPLC) Agilent Agilent1260 NMR Brooke 400MHz

[0031] The synthetic route of 3,5-difluoro-4-amino-4′-iodobiphenyl provided by the present invention is as follows: Step S1: 4-bromo-2,6-difluoroaniline (Compound 1), biboric acid pinacol ester (B2Pin2), a base and a solvent are mixed, and then heated to react in a nitrogen environment in the presence of a catalyst to prepare Compound 2. The synthetic route is as follows:

[0032]

[0033] Step S2: After mixing 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (Compound 2), 1-bromo-4-trimethylsilylbenzene and a base with a solvent, the temperature is raised and stirred in the presence of a catalyst under a nitrogen environment to prepare Compound 3.

[0034] The synthetic route is as follows:

[0035]

[0036] Step S3: Compound 3 is mixed with a solution of iodine chloride, and stirred at a certain temperature to react to obtain compound 4. The equivalent ratio of compound 3 to iodine chloride is 1:1-1:4, and the temperature is 0°C-25°C. The synthesis route of step S3 is as follows:

[0037]

[0038] <Preparation Example 1-10>

[0039] Each preparation example follows the synthetic route

[0040] Compound 2 was prepared, wherein the specific operation of Preparation Example 5 is:

[0041] Dimethyl sulfoxide (6L, 10V), 4-bromo-2,6-difluoroaniline (600g, 2.91mol, 1eq), bipyraclostrobin (967g, 3.78mol, 1.3eq) and potassium acetate (856g, 8.73mol, 3eq) were added to a 10L four-necked flask in sequence, and the nitrogen was replaced three times at room temperature; then 1,1-bis(diphenylphosphine)dichloroferrocene palladium (21.3g, 0.029mol, 0.01eq) was added at room temperature and the nitrogen was replaced three times to put the system in a nitrogen environment, the oil bath was heated to 90°C, and the reaction was carried out for 8 hours. HPLC test showed that the peak of compound 1 at 9.136min disappeared, and the peak of compound 2 at 10.167min appeared, indicating that the reaction was complete, and the reaction was stopped. The reaction solution was filtered through diatomaceous earth to obtain a reaction solution containing compound 2, which was directly used in the next step. The reaction solution of compound 2 obtained by filtration was characterized by HPLC, and the characterization data are shown in the attached figure. Figure 1 The reaction purity, i.e. the content of compound 2 in the reaction solution, was 69.53% as determined from the HPLC graph.

[0042] According to the method and steps of Preparation Example 5, other preparation examples obtained a series of results by changing the base, temperature and time of the reaction, as shown in Table 1. Among them, compound 1 was 2.91 mol, B2Pin2 was 3.78 mol, dimethyl sulfoxide was 6 L, and except for Preparation Example 10, the catalyst used was 1,1-bis(diphenylphosphine)diferropalladium dichloride dichloromethane complex, the other catalysts used were 1,1-bis(diphenylphosphine)diferropalladium dichloride. The yield is the separation yield, and the mass of compound 2 is calculated according to the HPLC percentage content.

[0043] Table 1 Feed ratios, reaction parameters and yields in step 1

[0044]

[0045]

[0046] <Preparation Examples 11-22>

[0047] Each preparation example follows the synthetic route

[0048] Compound 3 was prepared, wherein the specific operation of Preparation Example 15 is:

[0049] In a 10L four-necked flask, the reaction solution of compound 2 prepared in Preparation Example 5 (5L, 1.96mol, 1eq), an aqueous solution of potassium phosphate (830g, 3.92mol, 2eq, water: 1L, 2V) and 1-bromo-4-trimethylsilylbenzene (674g, 2.94mol, 1.5eq) were added in sequence, and nitrogen was replaced three times at room temperature; then 1,1-bis(diphenylphosphine)dichloroferrocene palladium (14.3g, 0.019mol, 0.01eq) was added at room temperature and nitrogen was replaced three times to place the system in a nitrogen environment, the oil bath was heated to 80°C, and the reaction was carried out for 8 hours. HPLC test showed that the peak of compound 2 at 10.167min disappeared (see Figure 3 ), indicating that compound 2 has been consumed and the reaction is complete. Stop the reaction and filter the reaction solution through diatomaceous earth. Then add 5 liters of water to the filtrate, extract twice with 2.5 liters of ethyl acetate, wash the organic phases with 2.5 liters of water, dry over anhydrous sodium sulfate, dry the solvent under reduced pressure, and pass through a column wet method to obtain 600 grams of crude product, which is crystallized at low temperature of 20°C to obtain brown solid compound 3 (500g, yield: 92%). Compound 3 was characterized by NMR, and the characterization data are shown in the attached Figure 2 : 1 H-NMR (400MHz, CDCl3); δ7.72-7.35(m,4H),7.21-7.05(m,2H),3.81(s,2H),0.33(s,9H).

[0050] According to the method and steps of Preparation Example 15, by changing the reaction base, temperature, time and catalyst equivalent, a series of results are obtained, as shown in Table 2. Among them, the yield is the separation yield. Compound 2 is 1.96 mol, 1-bromo-4-trimethylsilylbenzene is 2.94 mol, and dimethyl sulfoxide is 6 L. Except for the catalyst of Preparation Example 21, 1,1-bis(diphenylphosphine)diferropalladium dichloride dichloromethane complex is selected, and the remaining catalysts are 1,1-bis(diphenylphosphine)diferropalladium dichloride. The catalyst dosage of Preparation Example 21 is 0.057 mol, and the dosage of the remaining catalysts is 0.019 mol.

[0051] Table 2 Feed ratios, reaction parameters and yields in step 2

[0052] Preparation Example Base (1.5 equivalents) Temperature(℃) Response time (hours) Yield (%) 11 Potassium acetate 80 8 82 12 Sodium carbonate 80 8 79 13 Potassium acetate 80 8 63 14 Cesium carbonate 80 8 83 15 Potassium Phosphate 80 8 92 16 Potassium Phosphate 70 8 86 17 Potassium Phosphate 100 8 85 18 Potassium Phosphate 80 6 83 19 Potassium Phosphate 80 10 88 20 Potassium Phosphate 80 12 86 21 Potassium Phosphate 80 8 88 22 Potassium Phosphate 80 8 89

[0053] <Examples 1-6>

[0054] Each example prepared compound 4 according to the following synthetic route:

[0055] The specific operations of Example 2 are as follows:

[0056] Compound 3 (360 g, 1.3 mol, 1 eq) and dichloromethane (1.8 L, 5 V) were added to a 10 L three-necked flask in sequence. The atmosphere was replaced with nitrogen at room temperature. The reaction system was cooled to 0 °C using an ice bath. A dichloromethane solution of iodine chloride (253 g, 1.56 mol, 1.2 eq, dichloromethane: 1.8 L, 5 V) was slowly added dropwise at a temperature of 0 °C-5 °C. After the addition was completed, the temperature was naturally raised to room temperature and the reaction was continued for 0.5 hours. The peak of compound 3 at 12.302 min disappeared as monitored by HPLC, indicating that compound 3 was completely consumed (see Figure 4 ), then add sodium thiosulfate aqueous solution (0.5eq, 82g; water: 500mL) to quench the reaction, then add saturated sodium bicarbonate aqueous solution (1eq, 87g, water: 1000mL) to adjust the pH of the reaction system to 8-9. Then add 1000mL of water to separate the organic phase, and extract the aqueous phase with 1000mL of dichloromethane to obtain an organic phase. Combine the organic phases obtained twice, wash with saturated sodium chloride aqueous solution in turn, dry with anhydrous sodium sulfate, reduce the pressure to remove most of the liquid, and crystallize under dichloromethane (10v) at -20°C to obtain a solid product, namely the target product compound 4 (362g, yield: 84%). Compound 4 was used 1 H-NMR characterization, the characterization data of the compound is attached Figure 5 : 1 H-NMR (400MHz, CDCl3), δ7.72 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 7.04 (dd, J = 7.7, 1.9 Hz, 2H) 3.81 (s, 2H).

[0057] According to the method and steps of Example 2, by changing the equivalent of compound 3 and iodine chloride, the reaction temperature and time, a series of results were obtained, as shown in Table 3. Among them, the yield is the isolated yield. The compound 3 is 1.3 mol, and the dichloromethane is 1.8 L.

[0058] Table 3 Synthesis of compound 4 under various conditions

[0059] Serial number Iodine chloride Temperature(℃) Response time (hours) Yield (%) 1 1.0 0-25 1 60 2 1.2 0-25 1 84 3 1.5 0-25 1 76 4 2.0 0-25 1 70 5 3.0 0-25 1 65 6 4.0 0-25 1 68

[0060] The applicant declares that the above is only a specific implementation mode of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed by the present invention are within the protection scope and disclosure scope of the present invention.

Claims

1. A method for synthesizing 3,5-difluoro-4-amino-4'-iodobiphenyl, characterized in that: The synthetic route is as follows: ， The synthetic route comprises the following steps: Step S1, after mixing 4-bromo-2,6-difluoroaniline, bipyraclostrobin, a base and a solvent, adding a catalyst, and heating the mixture under an inert environment to obtain compound 2; Step S2, after mixing the compound 2, 1-bromo-4-trimethylsilylbenzene, a base and a solvent, adding a catalyst, heating and stirring under an inert environment to react to obtain compound 3, Step S3, mixing the compound 3 with an iodine chloride solution, stirring and reacting at a certain temperature in an inert environment to obtain the target product, namely 3,5-difluoro-4-amino-4'-iodobiphenyl.

2. The synthesis method according to claim 1, characterized in that In step S1, the inert environment is a nitrogen environment, the base is any one of potassium acetate, sodium carbonate, potassium carbonate or cesium carbonate, the solvent is dimethyl sulfoxide, and the catalyst is 1,1-bis(diphenylphosphine)diiron palladium dichloride or 1,1-bis(diphenylphosphine)diiron palladium dichloride dichloromethane complex.

3. The synthesis method according to claim 2, characterized in that In step S1, the equivalent ratio of the 4-bromo-2,6-difluoroaniline to the base is 1 to 2, the equivalent ratio of the 4-bromo-2,6-difluoroaniline to the catalyst is 0.01 to 0.03, and the temperature is raised to 80° C. to 100° C. for reaction for 6 h to 12 h.

4. The synthesis method according to claim 3, characterized in that In step S1, the base is potassium acetate, the equivalent ratio of potassium acetate to 4-bromo-2,6-difluoroaniline is 1.3, the catalyst is 1,1-bis(diphenylphosphine)dichloroferrocenepalladium, and the temperature is raised to 90° C. for reaction for 8 hours.

5. The synthesis method according to claim 1, characterized in that Step S1 prepares a reaction solution containing the compound 2, and the reaction solution is directly used for the reaction in step S2.

6. The synthesis method according to claim 1, characterized in that In step S2, the inert environment is a nitrogen environment, the base is any one of potassium acetate, sodium carbonate, potassium phosphate, cesium carbonate or potassium acetate, the solvent is dimethyl sulfoxide, and the catalyst is 1,1-bis(diphenylphosphine)diiron palladium dichloride or 1,1-bis(diphenylphosphine)diiron palladium dichloride dichloromethane complex.

7. The synthesis method according to claim 6, characterized in that In step S2, the equivalent ratio of the compound 2 to the 1-bromo-4-trimethylsilylbenzene is 1:1 to 1:2; the equivalent ratio of the compound 2 to the catalyst is 1:0.01 to 1:0.03, and the temperature is raised to 70°C to 100°C for reaction for 6h to 12h.

8. The synthesis method according to claim 7, characterized in that In step S2, the base is potassium phosphate, the equivalent ratio of the potassium phosphate to the compound 2 is 1.5, the catalyst is 1,1-bis(diphenylphosphine)diphenylferric palladium dichloride, and the temperature is raised to 80° C. for reaction for 8 hours.

9. The synthesis method according to claim 1, characterized in that In step S3, the equivalent ratio of the compound 3 to iodine chloride is 1:1 to 1:4, and the reaction temperature is 0°C to 25°C.

10. The synthesis method according to claim 1, characterized in that The specific operations of step S3 are: The compound 3 and dichloromethane were added to the reaction container, nitrogen was replaced at room temperature, and the reaction system was lowered to 0°C. The dichloromethane solution of iodine chloride was slowly added dropwise at 0°C to 5°C, and the reaction was carried out at room temperature for 0.5 hours. After the reaction was completed, an aqueous sodium thiosulfate solution was added to quench the reaction, and then a saturated sodium bicarbonate aqueous solution was added to adjust the pH of the reaction system to 8 to 9; water was added to separate the organic phase and collect the organic phase, and the aqueous phase was extracted with dichloromethane to obtain an organic phase, the organic phases obtained twice were combined, washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, most of the liquid was removed under reduced pressure, and the dichloromethane was crystallized at -20°C to obtain a solid product, i.e., the target product compound 4, wherein the dichloromethane solution of iodine chloride consisted of 253g iodine chloride and 1.8L dichloromethane, and the sodium thiosulfate aqueous solution consisted of 82g sodium thiosulfate and 500ml water.

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