A continuous synthesis method and device for m-terphenyl compounds

Abstract

The invention belongs to the technical field of continuous flow synthesis, and discloses a continuous synthesis method and device of a meta-terphenyl compound. The present invention uses a tetrahydrofuran solution of iodobenzene compounds, a tetrahydrofuran solution of isopropylmagnesium chloride·lithium chloride, and an aryl Grignard reagent solution as raw materials, and synthesizes the target product through magnesium halogen exchange reaction, elimination reaction and addition reaction. The technical scheme introduces isopropylmagnesium chloride·lithium chloride to carry out magnesium halogen exchange reaction, and mild reaction conditions make the multiple elementary reactions involved in the reaction proceed in order, solves the problem that the coexistence of multiple elementary reactions of high-activity Grignard reagents under intermittent conditions is difficult to control, and the generation amount and type of waste are controlled, and the product yield is stabilized at 80 95%. In addition, the continuous process reduces the amount of aryl Grignard reagents with higher cost. Therefore, the synthesis method of the present invention has the advantages of low cost, simple operation, high time and space efficiency, and low discharge of three wastes.

Description

Technical Field

[0001] The invention belongs to the technical field of continuous flow synthesis, and in particular relates to a continuous synthesis method and device for m-terphenyl compounds. Background Art

[0002] Terphenyl compounds, namely 3,5-diaryl substituted benzene, have a large conjugated system formed by three benzene rings connected together, which has unique advantages in the conduction of photoelectricity. At the same time, this type of compound has a planar structure and molecules are easy to aggregate and crystallize. These characteristics greatly improve its practical application value in organic electroluminescent devices. In addition, 3,5-diaryl substituted benzene is also widely used in ligand design and synthesis due to its unique spatial structure, such as the following structure:

[0003]

[0004] Although 3,5-diaryl substituted benzenes are widely used in many fields, their synthesis is less studied. There are mainly three schemes: condensation reaction of Grignard reagents and halogens, Suzuki-Miyaura reaction, and benzyne intermediate reaction. The first two schemes require metals as catalysts and introduce heavy metals into the reaction system. In addition, these two schemes need to complete the coupling reaction at the 3rd and 5th positions, but there are three Br in iodobenzene compounds that can be used as reaction sites, which leads to the simultaneous existence of single coupling, double coupling, and triple coupling products in the reaction results, which brings great challenges to the post-processing and yield of the reaction (the yield is generally 20-60%). The method for synthesizing 3,5-diaryl substituted benzene compounds by coupling reaction is as follows:

[0005] .

[0006] The third scheme is to start with a magnesium halogen exchange reaction, then determine the regioselectivity of the reaction, and then obtain the target product through two elimination reactions of ortho-halogen Grignard reagents and addition reactions of benzyne intermediates. This scheme effectively improves the regioselectivity of the reaction. This reaction usually requires 3.5-5.0 equivalents of aromatic Grignard reagents to participate in the reaction, of which only 2.0 equivalents of Grignard reagents are necessary for product synthesis. The use of excessive aromatic Grignard reagents will produce by-products, and post-treatment requires column chromatography for purification. In addition, conventional aromatic Grignard reagents require relatively harsh conditions such as reflux for magnesium halogen exchange reactions, which are difficult to operate and difficult to control reaction selectivity. The method for synthesizing 3,5-bis-aryl substituted benzene compounds using Grignard reagents is as follows:

[0007] .

[0008] Therefore, in order to meet the broad market demand, it is urgently necessary to develop a green, stable, efficient and scalable production process for terphenyl compounds, in order to reduce their cost of use and promote their widespread application in optoelectronic materials and ligands. Summary of the invention

[0009] In order to solve the shortcomings and deficiencies of the above-mentioned prior art, such as long process flow, complex processing operation, low safety factor, high production cost and low production efficiency, the primary purpose of the present invention is to provide a continuous synthesis method of terphenyl compounds, thereby realizing the green, safe and efficient full-continuous preparation of such compounds.

[0010] Another object of the present invention is to provide a device for implementing the above-mentioned continuous synthesis method.

[0011] To achieve the above object, the present invention adopts the following technical solution:

[0012] A continuous synthesis method of a m-terphenyl compound comprises the following steps:

[0013] Step S1: using a tetrahydrofuran solution of an iodobenzene compound as feed liquid A and a tetrahydrofuran solution of isopropylmagnesium chloride·lithium chloride as feed liquid B; mixing feed liquid A and feed liquid B and performing a magnesium halogen exchange reaction to obtain a reaction liquid D;

[0014] The concentration of the iodobenzene compound in the feed liquid A is 0.65-1.3 mol / L, preferably 0.65 mol / L or 1.3 mol / L; the concentration of isopropylmagnesium chloride·lithium chloride in the feed liquid B is 1.3 mol / L; the molar ratio of the iodobenzene compound to isopropylmagnesium chloride·lithium chloride is 1:1-1.3;

[0015] Step S2: using an aryl Grignard reagent solution as a feed solution C, mixing the feed solution C and the reaction solution D, and then sequentially performing a primary elimination reaction, a primary addition reaction, a secondary elimination reaction and a secondary addition reaction at 80-100° C. to obtain a reaction solution E;

[0016] The concentration of the aromatic Grignard reagent solution is 0.5-2.0 mol / L; the molar ratio of the iodobenzene compound in step S1 to the aromatic Grignard reagent in step S2 is 1:2.1-2.5;

[0017] Step S3: receiving and quenching the reaction solution E with a saturated aqueous solution of ammonium chloride, and then obtaining the target product, a m-terphenyl compound, after separation, drying, concentration and recrystallization.

[0018] The iodobenzene compound has a structure as shown in the following formula I; the intermediate product contained in the reaction solution D has a structure as shown in the following formula II; the intermediate product contained in the reaction solution E has a structure as shown in the following formula III; the target product m-terphenyl compound has a structure as shown in the following formula IV:

[0019] ;

[0020] Here, X is a chlorine atom or a bromine atom, and R is a hydrogen atom, a chlorine atom or a bromine atom.

[0021] The aryl Grignard reagent solution in step S2 is a tetrahydrofuran or 2-methyl-tetrahydrofuran solution of an aryl Grignard reagent (chemical formula is ArMgX, X is chlorine or bromine).

[0022] A device for realizing the above-mentioned continuous synthesis method of m-terphenyl compounds, the device comprising a first feed pump, a second feed pump, a third feed pump, a first mixer, a second mixer, a first microreactor, a second microreactor, a back pressure valve and a receiving device; wherein the first feed pump and the second feed pump are respectively connected to the first mixer by a pipeline, the first mixer is connected to the first microreactor by a pipeline, the third feed pump and the first microreactor are respectively connected to the second mixer by a pipeline, and the second mixer, the second microreactor, the back pressure valve and the receiving device are sequentially connected by a pipeline;

[0023] The device is used to continuously synthesize terphenyl compounds. The specific process conditions are as follows: feed liquid A is fed by a first feed pump, and feed liquid B is fed by a second feed pump, so that feed liquid A and feed liquid B are simultaneously pumped into a first microreactor through a first mixer to perform a magnesium halogen exchange reaction to obtain a reaction liquid D; the reaction liquid D flows out of the first microreactor and enters a second mixer, while feed liquid C is fed by a third feed pump into the second mixer to mix with the reaction liquid D, and the obtained mixed solution continues to flow into the second microreactor, and the second microreactor is heated. The reaction liquid D undergoes a primary elimination reaction, the intermediate product 1 undergoes a primary addition reaction with part of the aryl Grignard reagent in the feed liquid C, the intermediate product 2 undergoes a secondary elimination reaction, and the intermediate product 3 undergoes a secondary addition reaction with the remaining aryl Grignard reagent in the feed liquid C, and finally obtains the reaction liquid E; the reaction liquid E flowing out through the back pressure valve is received and quenched by a receiving device filled with a saturated ammonium chloride aqueous solution, and then the target product m-terphenyl compound is obtained after liquid separation, drying, concentration and purification;

[0024] The intermediate product 1 has a structure as shown in the following formula V, the intermediate product 2 has a structure as shown in the following formula VI, and the intermediate product 3 has a structure as shown in the following formula VII, wherein X is a chlorine atom or a bromine atom, and R is a hydrogen atom, a chlorine atom or a bromine atom:

[0025] .

[0026] The retention time of the reaction solution D in the first microreactor is 40-120 seconds; the reaction temperature of the reaction solution D in the first microreactor is -10-25°C.

[0027] The retention time of the reaction solution E in the second microreactor is 8-16 minutes; the reaction temperature of the reaction solution E in the second microreactor is 80-100°C.

[0028] The equation for the above continuous synthesis method is as follows:

[0029] .

[0030] Here, X is a chlorine atom or a bromine atom, and R is a hydrogen atom, a chlorine atom or a bromine atom.

[0031] Compared with the prior art, the present invention has the following advantages and effects:

[0032] (1) The technical solution of the present invention analyzes the reaction process, introduces isopropylmagnesium chloride·lithium chloride to carry out magnesium halide exchange reaction, reduces the reflux reaction conditions required in the traditional solution to room temperature or low temperature, and allows multiple elementary reactions involved in the reaction to proceed in an orderly manner, thereby solving the problem that multiple elementary reactions of highly active Grignard reagents are difficult to control under intermittent conditions, and the amount and type of waste generated are controlled, and the product yield is stabilized at 80-95%.

[0033] (2) The technical solution of the present invention uses isopropylmagnesium chloride·lithium chloride to carry out magnesium halogen exchange reaction, which reduces the demand for 1 equivalent of aryl Grignard reagent. In addition, the continuous reaction effectively improves the reaction selectivity of the Grignard reagent, both of which effectively reduce the use of aryl Grignard reagent. While simplifying the post-processing operation, the economic cost brought by the aryl Grignard reagent is effectively reduced.

[0034] (3) The technical solution of the present invention has high operational safety based on continuous flow technology. The use of microreactors to synthesize m-terphenyl compounds simplifies the experimental operation process. The microreactor has efficient heat and mass transfer capabilities and no amplification effect. Its production capacity has a large elastic range. It is a green, environmentally friendly, economical and efficient method for producing m-terphenyl compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 Schematic diagram of the device for realizing the continuous synthesis method of m-terphenyl compounds of the present invention, wherein 1 is the first feed pump, 2 is the second feed pump, 3 is the third feed pump, 4 is the first mixer, 5 is the second mixer, 6 is the first microreactor, 7 is the second microreactor, 8 is the back pressure valve, 9 is the receiving device, and 10 is the flow direction of the reaction liquid. DETAILED DESCRIPTION

[0036] The present invention is further described in detail below in conjunction with embodiments so that those skilled in the art can implement the invention with reference to the description.

[0037] It should be understood that the terms such as “having”, “including” and “comprising” used herein do not exclude the existence or addition of one or more other elements or combinations thereof.

[0038] The test methods used in the following examples are conventional methods unless otherwise specified. The materials and reagents used in the following examples are all commercially available unless otherwise specified. In the following examples, if no specific conditions are specified, the experiments were carried out under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used, if the manufacturer is not specified, are all conventional products that can be purchased commercially.

[0039] In the following examples, if no specific techniques or conditions are specified, the techniques and conditions described in the literature in the field or in the product instructions are used; the reagents and instruments used below are all conventional products available on the market; the amounts of the compounds used in the following examples are measured in equivalents.

[0040] 1. The synthesis method of the aryl Grignard reagent in the following examples is as follows:

[0041] Take a three-necked round-bottom flask, equip it with a stirrer, a constant pressure dropping funnel, a vacuum connector and a reflux tube, dry it, assemble it into a reaction device, and then protect it with nitrogen. Then, add magnesium chips (1.2 equivalents) and iodine (0.02 equivalents) to the three-necked round-bottom flask under a nitrogen atmosphere, close the reaction system, and then add the solvent tetrahydrofuran to the three-necked round-bottom flask through a double-ended needle, and transfer the tetrahydrofuran solution of the aryl halide (1 equivalent) to the constant pressure dropping funnel. The reaction device is stirred at room temperature, heated to reflux with a hair dryer, and after reflux for 10 minutes, the tetrahydrofuran solution of the aryl halide is added dropwise, and the reaction solution gradually turns grayish white, and then the remaining tetrahydrofuran solution of the aryl halide is added dropwise under stirring at room temperature. After the addition is complete, continue stirring at room temperature for 2 hours. After the reaction is completed, the reaction solution is calibrated and prepared to the set concentration.

[0042] 2. The device used in the continuous synthesis method of m-terphenyl compounds in the following examples has the following structure:

[0043] The device comprises a first feed pump 1, a second feed pump 2, a third feed pump 3, a first mixer 4, a second mixer 5, a first microreactor 6, a second microreactor 7, a back pressure valve 8 and a receiving device 9; wherein the first feed pump 1 and the second feed pump 2 are respectively connected to the first mixer 4 by a pipeline, the first mixer 4 is connected to the first microreactor 6 by a pipeline, the third feed pump 3 and the first microreactor 6 are respectively connected to the second mixer 5 by a pipeline, and the second mixer 5, the second microreactor 7, the back pressure valve 8 and the receiving device 9 are sequentially connected by a pipeline;

[0044] The device is used to continuously synthesize terphenyl compounds. The specific process conditions are as follows: feed liquid A is fed by a first feed pump, and feed liquid B is fed by a second feed pump, so that feed liquid A and feed liquid B are simultaneously pumped into a first microreactor through a first mixer to perform a magnesium halogen exchange reaction to obtain a reaction liquid D; the reaction liquid D flows out of the first microreactor and enters a second mixer, while feed liquid C is fed by a third feed pump into the second mixer to mix with the reaction liquid D, and the obtained mixed solution continues to flow into the second microreactor, and the second microreactor is heated. The reaction liquid D undergoes a primary elimination reaction, the intermediate product 1 undergoes a primary addition reaction with part of the aryl Grignard reagent in the feed liquid C, the intermediate product 2 undergoes a secondary elimination reaction, and the intermediate product 3 undergoes a secondary addition reaction with the remaining aryl Grignard reagent in the feed liquid C, and finally obtains the reaction liquid E; the reaction liquid E flowing out through the back pressure valve is received and quenched by a receiving device filled with a saturated ammonium chloride aqueous solution, and then the target product m-terphenyl compound is obtained after liquid separation, drying, concentration and purification;

[0045] The intermediate product 1 has a structure as shown in the following formula V, the intermediate product 2 has a structure as shown in the following formula VI, and the intermediate product 3 has a structure as shown in the following formula VII, wherein X is a chlorine atom or a bromine atom, and R is a hydrogen atom, a chlorine atom or a bromine atom:

[0046] .

[0047] The following Examples 1-12 studied the effects of reaction temperature, retention time, molar ratio of feed, and feed liquid concentration on the reaction effect through the synthesis of 3,5-diphenylbromobenzene. Example 1-3 used different retention times and reaction temperatures for magnesium halogen exchange reaction, i.e., the reaction occurred in the first microreactor; the feed molar ratio of magnesium halogen exchange reaction in Examples 1, 4-5 was different; the feed concentration of iodobenzene compound in Examples 1 and 6 was different; Example 1, 7-8 used different retention times and reaction temperatures for elimination reaction and addition reaction, i.e., the reaction occurred in the second microreactor; the amount of aryl Grignard reagent in Example 1, 9-10 was different; the feed liquid concentration of aryl Grignard reagent in Example 1, 11-12 was different.

[0048] The synthesis reaction of 3,5-diphenylbromobenzene in Example 1-12 is as follows:

[0049] .

[0050] Example 1

[0051] Preparation of feed solution: Weigh 72 g (162.5 mmol) of iodobenzene compound 2,4,6-tribromoiodobenzene and add it into a three-necked round-bottom flask. Under a nitrogen atmosphere, dissolve it with tetrahydrofuran and make the volume to 250 mL to obtain feed solution A with a concentration of 0.65 mol / L; commercial isopropylmagnesium chloride·lithium chloride tetrahydrofuran solution (1.3 mol / L) is used as feed solution B; phenylmagnesium chloride tetrahydrofuran solution (1 mol / L) is used as feed solution C.

[0052] Pump flow rate parameter settings: the flow rate of the first feed pump pumping feed liquid A is 2 mL / min, the flow rate of the second feed pump pumping feed liquid B is 1.1 mL / min, and the flow rate of the third feed pump pumping feed liquid C is 3 mL / min.

[0053] Microreactor parameter settings: the retention volume of the first microreactor was 4.2 mL, the reaction temperature was 0 °C, and the residence time was 81 s; the retention volume of the second microreactor was 50 mL, the reaction temperature was 100 °C, and the residence time was 8 min.

[0054] Feeding molar ratio:

[0055] The molar ratio of 2,4,6-tribromoiodobenzene to isopropylmagnesium chloride·lithium chloride is 1:1.1;

[0056] The molar ratio of 2,4,6-tribromoiodobenzene to phenylmagnesium chloride is 1:2.3.

[0057] Continuous synthesis process:

[0058] Feed liquid A is fed by a first feed pump, and feed liquid B is fed by a second feed pump, so that feed liquid A and feed liquid B are simultaneously pumped into a first microreactor through a first mixer to perform a magnesium halide exchange reaction to obtain a reaction liquid D; the reaction liquid D flows out of the first microreactor and enters a second mixer, while the feed liquid C is fed into the second mixer by a third feed pump to mix with the reaction liquid D, and the obtained mixed solution continues to flow into the second microreactor, and the second microreactor is heated to 80-100° C., the reaction liquid D undergoes a primary elimination reaction, the obtained intermediate product 1 undergoes a primary addition reaction with part of the aromatic Grignard reagent in the feed liquid C, the obtained intermediate product 2 continues to undergo a secondary elimination reaction, and the obtained intermediate product 3 continues to undergo a secondary addition reaction with the remaining aromatic Grignard reagent in the feed liquid C, and finally a reaction liquid E is obtained; the reaction liquid E flowing out through the back pressure valve is received by a receiving device equipped with a saturated aqueous ammonium chloride solution to complete quenching.

[0059] Post-treatment and product purification: The reaction solution in the receiving device was allowed to stand for stratification to obtain an organic phase, which was dried, concentrated and the solvent tetrahydrofuran was recovered. Methanol was added to the residue, and crystals were precipitated by ultrasound. The white solid product was obtained by filtration with a yield of 92% and a purity of more than 99% according to HPLC analysis. The obtained product was characterized, and the data results were as follows, confirming that the compound was 3,5-diphenylbromobenzene:

[0060] 1 H NMR (400 MHz, Chloroform-d) δ 7.73 (bs, 3H), 7.65 (d, J = 7.8 Hz, 4H), 7.50 (t, 4H), 7.43 (t, J = 7.7 Hz, 2H). 13 C NMR (101 MHz, Chloroform-d) δ143.71, 139.80, 128.97, 128.04, 127.26, 124.89, 123.29.

[0061] Example 2

[0062] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0063] The retention volume of the first microreactor was 6.2 mL, the reaction temperature was -10 °C, and the residence time was 120 s. The product 3,5-diphenylbromobenzene obtained in this example was a white solid product with a yield of 91% and a purity of more than 99% according to HPLC analysis.

[0064] Example 3

[0065] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0066] The retention volume of the first microreactor was 2 mL, the reaction temperature was 25° C., and the residence time was 40 s. The product 3,5-diphenylbromobenzene obtained in this example was a white solid product with a yield of 87% and a purity of greater than 99% according to HPLC analysis.

[0067] Example 4

[0068] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0069] The flow rate of the first feed pump pumping feed liquid A is 2.0 mL / min, and the flow rate of the second feed pump pumping feed liquid B is 1.0 mL / min, that is, the molar ratio of 2,4,6-tribromoiodobenzene to isopropylmagnesium chloride·lithium chloride is 1: 1. The product 3,5-diphenylbromobenzene obtained in this embodiment is a white solid product with a yield of 83% and a purity of more than 99% according to HPLC analysis.

[0070] Example 5

[0071] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0072] The flow rate of the first feed pump pumping feed liquid A is 2.0 mL / min, and the flow rate of the second feed pump pumping feed liquid B is 1.3 mL / min, that is, the molar ratio of 2,4,6-tribromoiodobenzene to isopropylmagnesium chloride·lithium chloride is 1:1.3. The product 3,5-diphenylbromobenzene obtained in this embodiment is a milky white solid product with a yield of 85% and a purity of 97% by HPLC analysis.

[0073] Example 6

[0074] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0075] The concentration of 2,4,6-tribromoiodobenzene in feed liquid A is 1.3 mol / L, the flow rate of the first feed pump pumping feed liquid A is 1.0 mL / min, and the retention volume of the first microreactor is 2.8 mL. The product 3,5-diphenylbromobenzene obtained in this example is a milky white solid product with a yield of 90% and a purity of greater than 99% by HPLC analysis.

[0076] Example 7

[0077] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0078] The retention volume of the second microreactor was 75 mL, the reaction temperature was 90° C., and the residence time was 12 min. The product 3,5-diphenylbromobenzene obtained in this example was a white solid product with a yield of 92% and a purity of greater than 99% according to HPLC analysis.

[0079] Example 8

[0080] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0081] The retention volume of the second microreactor was 100 mL, the reaction temperature was 80° C., and the residence time was 16 min. The product 3,5-diphenylbromobenzene obtained in this example was a white solid product with a yield of 91% and a purity of greater than 99% according to HPLC analysis.

[0082] Example 9

[0083] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0084] The flow rate of the third feed pump for pumping feed liquid C is 2.7 mL / min, that is, the molar ratio of 2,4,6-tribromoiodobenzene to phenylmagnesium chloride is 1:2.1. The product 3,5-diphenylbromobenzene obtained in this embodiment is a white solid product with a yield of 86% and a purity of more than 99% according to HPLC analysis.

[0085] Example 10

[0086] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0087] The flow rate of the third feed pump for pumping feed liquid C is 3.3 mL / min, that is, the molar ratio of 2,4,6-tribromoiodobenzene to phenylmagnesium chloride is 1:2.5. The product 3,5-diphenylbromobenzene obtained in this embodiment is a white solid product with a yield of 92% and a purity of 98% according to HPLC analysis.

[0088] Embodiment 11

[0089] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0090] The concentration of phenylmagnesium chloride in the feed liquid C is 0.5 mol / L, the flow rate of the third feed pump for pumping the feed liquid C is 6.0 mL / min, and the retention volume of the second microreactor is 100 mL. The product 3,5-diphenylbromobenzene obtained in this embodiment is a milky white solid product with a yield of 90% and a purity of greater than 99% by HPLC analysis.

[0091] Example 12

[0092] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0093] The concentration of phenylmagnesium chloride in the feed liquid C is 2 mol / L, the flow rate of the third feed pump for pumping the feed liquid C is 1.5 mL / min, and the retention volume of the second microreactor is 36.8 mL. The product 3,5-diphenylbromobenzene obtained in this example is a milky white solid product with a yield of 91% and a purity of more than 99% according to HPLC analysis.

[0094] The target product BP was prepared by Examples 13-27. The operation of Examples 13-27 was basically the same as that of Example 1, except that different types of aromatic Grignard reagents were used. See Tables 1 and 2 below for details.

[0095] Table 1 Product yields of Examples 13-20

[0096]

[0097] Table 2 Product yields of Examples 21-27

[0098]

[0099] Example 13 The structural formula of target product B:

[0100]

[0101] The target product B has a yield of 88%, a white solid, and a purity of greater than 99% by HPLC. The obtained product was characterized, and the results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.23 (s, 1H), 7.16 (d, J = 1.9Hz, 2H), 6.00 (t, J = 1.8 Hz, 4H), 2.11 (s, 6H), 1.89 (d, J = 1.7 Hz, 12H). 13 CNMR (101 MHz, Chloroform-d) δ 153.87, 149.77, 146.22, 138.12, 132.10, 123.98, 116.72, 115.13, 60.60, 52.83, 21.80, 19.03.

[0102] Example 14 The structural formula of target product C:

[0103]

[0104] The target product C has a yield of 92%, a white solid, and a purity of greater than 99% by HPLC. The obtained product was characterized, and the results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.35 (d, J = 1.4 Hz, 2H), 7.05(s, 4H), 6.98 (t, J = 1.5 Hz, 1H), 2.94 (hept, J = 7.0 Hz, 2H), 1.30 (d, J =6.9 Hz, 12H), 1.17 (d, J = 6.8 Hz, 12H), 1.06 (d, J = 6.9 Hz, 11H). 13 C NMR (101 MHz, Chloroform-d) δ 148.36, 146.36, 142.61, 135.42, 130.70, 130.37, 121.91, 120.58, 34.31, 30.46, 24.35, 24.08.

[0105] Example 15 The structural formula of target product D:

[0106]

[0107] The yield of the target product D was 87%, and the product was a white solid with a purity of more than 99% according to HPLC. The obtained product was characterized and the results were as follows: 1H NMR (400 MHz, Chloroform-d) δ 8.26 (s, 1H), 7.87 (dd, J = 6.2,3.3 Hz, 5H), 7.82-7.79 (m, 1H), 7.74-7.72 (m, 2H), 7.51 (dd, J = 6.3, 3.3 Hz,8H). 13 C NMR (126 MHz, Chloroform-d) δ 143.76, 137.13, 133.70, 133.05, 129.32,128.85, 128.44, 127.84, 126.68, 126.50, 126.31, 125.40, 123.59.

[0108] Example 16 The structural formula of the target product E:

[0109]

[0110] The target product E has a yield of 81%, a white solid, and a purity of greater than 99% by HPLC. The obtained product was characterized, and the results are as follows:1 H NMR (400 MHz, Chloroform-d) δ 7.79 (d, J = 9.2 Hz, 2H), 7.71-7.63 (m, 4H), 7.52 (s, 2H), 7.37 (s, 1H), 7.31 (s, 1H), 7.30-7.26 (m, 7H). 13 CNMR (101 MHz, Chloroform-d) δ 142.72, 138.49, 133.86, 131.78, 131.38, 130.59,128.48, 128.36, 127.21, 126.50, 126.04, 125.64, 125.39, 122.28.

[0111] Example 17 The structural formula of the target product F:

[0112]

[0113] The target product F has a yield of 86%, a white solid, and a purity of greater than 99% by HPLC. The obtained product was characterized, and the results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.82-7.75 (m, 3H), 7.59 (t, J =1.8 Hz, 2H), 7.52 (d, J = 1.8 Hz, 4H), 1.48 (s, 36H). 13 C NMR (101 MHz, Chloroform-d) δ 151.54, 145.08, 139.67, 129.10, 125.79, 123.01, 122.21,121.92, 35.14, 31.65.

[0114] Example 18 The structural formula of the target product G is:

[0115]

[0116] The yield of the target product G was 79%, and it was a white solid with a purity of more than 99% according to HPLC. The obtained product was characterized, and the results were as follows: 1H NMR (400 MHz, Chloroform-d) δ 7.70 (d, J = 1.6 Hz, 2H), 7.60 (t, J = 1.7 Hz, 1H), 7.14-7.09 (m, 4H), 6.85 (tt, J = 8.8, 2.3 Hz, 2H). 13 C NMR(101 MHz, Chloroform-d) δ 164.63 (d, J = 12.9 Hz), 162.15 (d, J = 13.0 Hz),142.52, 141.61, 129.93, 124.53, 123.71, 111.07-109.60 (m), 103.56 (t, J =25.3 Hz).

[0117] Example 19 The structural formula of the target product H is:

[0118]

[0119] The yield of the target product H was 90%, white solid, and the HPLC purity analysis was greater than 99%. The obtained product was characterized, and the results were as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.73 (s, 3H), 7.28 (s, 4H), 7.09 (s, 2H), 2.45 (s, 12H). 13 C NMR (101 MHz, Chloroform-d) δ 143.86, 139.88, 138.50, 129.62, 128.78, 125.16, 124.89, 123.07, 21.45.

[0120] Example 20 The structural formula of the target product I:

[0121]

[0122] The target product I had a yield of 84%, a white solid, and a purity of greater than 99% according to HPLC. The obtained product was characterized, and the results were as follows: 1H NMR (400 MHz, Chloroform-d) δ 7.62 (s, 3H), 7.28 (t, J = 7.9Hz, 2H), 7.10 (d, J = 6.9 Hz, 2H), 7.07-7.02 (m, 2H), 6.85 (dd, J = 8.8, 3.0Hz, 2H), 3.77 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 160.11, 143.57, 141.24, 130.03, 129.14, 124.96, 123.26, 119.75, 113.47, 113.03, 55.41.

[0123] Example 21 The structural formula of target product J:

[0124]

[0125] The target product J has a yield of 85%, a white solid, and a purity of greater than 99% by HPLC. The obtained product was characterized, and the results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.67 (d, J = 1.5 Hz, 2H), 7.63(t, J = 1.6 Hz, 1H), 7.35 (ddd, J = 7.4, 5.8, 1.8 Hz, 4H), 7.05 (t, J = 7.5Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 3.85 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 156.47, 140.04, 130.92 (d, J = 4.4 Hz), 129.57, 129.36, 129.16, 121.53,120.90, 111.26, 55.62.

[0126] Example 22 The structural formula of the target product K:

[0127]

[0128] The target product K had a yield of 88%, a white solid, and a purity of more than 99% by HPLC. The obtained product was characterized, and the results were as follows: 1H NMR (400 MHz, Chloroform-d) δ 7.63 (s, 3H), 7.55 (d, J = 8.8Hz, 4H), 7.03-6.97 (m, 4H), 3.86 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ159.67, 143.23, 132.34, 128.28, 127.90, 123.95, 123.24, 114.37, 55.40.

[0129] Example 23 The structural formula of the target product L:

[0130]

[0131] The target product L has a yield of 82%, a white solid, and a purity of greater than 99% by HPLC. The obtained product was characterized, and the results are as follows: 1 H NMR (500 MHz, Chloroform-d) δ 7.66 (d, J = 1.6 Hz, 2H), 7.60 (t, J = 1.6 Hz, 1H), 7.52 (d, J = 8.5 Hz, 4H), 7.43 (d, J = 8.5 Hz, 4H). 13 CNMR (126 MHz, Chloroform-d) δ 142.65, 138.07, 134.41, 129.25, 129.14, 128.54,124.53, 123.58.

[0132] Example 24 The structural formula of the target product M:

[0133]

[0134] The target product M has a yield of 83%, a white solid, and a purity of greater than 99% by HPLC. The obtained product was characterized, and the results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.64 (d, J = 1.6 Hz, 2H), 7.59 (t, J = 1.6 Hz, 1H), 7.58-7.52 (m, 4H), 7.16 (t, J = 8.7 Hz, 4H). 13C NMR (101MHz, Chloroform-d) δ 164.12, 161.66, 142.72, 135.75 (d, J = 3.3 Hz), 128.85 (d, J = 8.4 Hz), 124.53, 123.39, 115.92 (d, J = 21.6 Hz).

[0135] Example 25 The structural formula of the target product N is:

[0136]

[0137] The yield of the target product N was 73%, white solid, and the HPLC purity analysis was greater than 99%. The obtained product was characterized, and the results were as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.69 (d, J = 1.6 Hz, 2H), 7.61 (dd, J = 8.8, 2.2 Hz, 5H), 7.32 (d, J = 7.6 Hz, 4H). 13 C NMR (101 MHz, Chloroform-d) δ 149.27 (d, J = 1.9 Hz), 142.44, 138.23, 129.29, 128.62, 124.72, 123.51, 121.41.

[0138] Example 26 The structural formula of the target product O is:

[0139]

[0140] The yield of target compound O was 76%, white solid, and the HPLC purity analysis was greater than 99%. The obtained product was characterized, and the results were as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.78 (d, J = 8.5 Hz, 2H), 7.62 (dd, J = 8.3, 1.3 Hz, 5H), 7.57 (dd, J = 8.3, 1.4 Hz, 2H), 7.46 (td, J = 7.4,2.1 Hz, 7H), 7.41 -7.37 (m, 3H), 7.35 (d, J = 8.5 Hz, 2H). 13C NMR (101 MHz, Chloroform-d) δ 141.27, 140.76, 140.10, 137.88, 129.05, 128.94, 128.79, 127.73, 127.29, 127.20, 126.94.

[0141] Example 27 The structural formula of the target product P:

[0142]

[0143] The target product P had a yield of 86%, a white solid, and a purity of more than 99% according to HPLC. The obtained product was characterized, and the results were as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.59 (t, J = 1.6 Hz, 1H), 7.56(d, J = 1.6 Hz, 2H), 7.42 (d, J = 8.5 Hz, 4H), 7.36 (d, J = 8.5 Hz, 4H), 1.25(s, 18H). 13 C NMR (101 MHz, Chloroform-d) δ 151.11, 143.51, 136.98, 128.58, 126.91, 125.93, 124.58, 123.22, 34.66, 31.41.

[0144] The target product QR was prepared by Examples 28-29. The operation of Examples 28-29 was basically the same as that of Example 1, except that the types of iodobenzene compounds were different, as shown in Table 3 below.

[0145] Table 3 Product yields of Examples 28-29

[0146]

[0147] Example 28 The structural formula of the target product Q:

[0148]

[0149] The target product Q has a yield of 93%, a white solid, and a purity of greater than 99% by HPLC. The obtained product was characterized, and the results are as follows: 1H NMR (400 MHz, Chloroform-d) δ 7.35 (t, J = 7.5 Hz, 2H), 7.42(t, J = 7.5 Hz, 4H), 7.47-7.50 (m, 1H), 7.55 (dd, J = 7.0, 1.5 Hz, 2H), 7.61-7.64 (m, 4H), 7.80 (t, J = 1.5 Hz, 1H). 13 C NMR (101 MHz, Chloroform-d) δ141.9, 141.3, 129.3, 128.9, 127.5, 127.4, 126.3, 126.2.

[0150] Example 29 The structural formula of the target product R:

[0151]

[0152] The target product R has a yield of 91%, a white solid, and a purity of greater than 99% by HPLC. The obtained product was characterized, and the results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.87 (d, J = 1.6 Hz, 2H), 7.61(s, 1H), 7.55 (d, J = 8.5 Hz, 4H), 7.43 (d, J = 8.5 Hz, 4H), 7.38 (m, 2H).13CNMR (126 MHz, Chloroform-d) δ 140.8, 137.1, 133.4, 128.3, 128.1, 127.5,125.9, 124.3.

[0153] Example 30 The structural formula of the target product Q is:

[0154]

[0155] The target product Q had a yield of 87%, a white solid, and a purity of more than 99% according to HPLC. The obtained product was characterized, and the results were as follows: 1H NMR (400 MHz, Chloroform-d) δ 7.35 (t, J = 7.5 Hz, 2H), 7.42(t, J = 7.5 Hz, 4H), 7.47-7.50 (m, 1H), 7.55 (dd, J = 7.0, 1.5 Hz, 2H), 7.61-7.64 (m, 4H), 7.80 (t, J = 1.5 Hz, 1H). 13 C NMR (101 MHz, Chloroform-d) δ141.9, 141.3, 129.3, 128.9, 127.5, 127.4, 126.3, 126.2.

[0156] Compared with the embodiments of the present invention, Comparative Examples 1-2 use an intermittent process to synthesize compounds A and C, and are compared with the technical route of the present invention in terms of experimental operation, product yield and economic effect, proving the creativity and beneficial effects of the present invention.

[0157] Comparative Example 1 Existing route to synthesize target compound A

[0158] The existing route for synthesizing target compound A is as follows:

[0159] .

[0160] 1) Take a three-necked round-bottom flask, equip it with a stirring bar, a constant pressure dropping funnel, a vacuum connector and a reflux tube, dry it, assemble it into a reaction device and protect it with nitrogen. Then, under a nitrogen atmosphere, add 120 mL of a tetrahydrofuran solution of phenylmagnesium chloride (2.5 mol / L, commercialized) to the three-necked round-bottom flask, add 60 mL of a tetrahydrofuran solution of 2,4,6-tribromoiodobenzene (1.0 mol / L) to the constant pressure dropping funnel, heat the three-necked round-bottom flask to reflux, start to drop the tetrahydrofuran solution of 2,4,6-tribromoiodobenzene, and complete the dropwise addition in about 1 hour. Continue the reflux reaction for 12 hours.

[0161] 2) After the reaction was completed, 200 mL of saturated ammonium chloride was used to quench the reaction, and the mixture was transferred to a separatory funnel. The organic phase was collected, and the aqueous phase was washed with dichloromethane (3×100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. Methanol was added to the residue, and crystallization was performed by ultrasonication. The target compound A was obtained by filtration with a yield of 76% as a white solid. The HPLC purity analysis was 94%.

[0162] Comparative Example 2 Existing route to synthesize target compound C

[0163] The existing route for synthesizing target compound C is as follows:

[0164] .

[0165] 1) Take a three-necked round-bottom flask, equip it with a stirring bar, a constant-pressure dropping funnel, a vacuum connector and a reflux tube, dry it, assemble it into a reaction device and protect it with nitrogen. Then, under a nitrogen atmosphere, add magnesium chips (7.2 g, 300 mmol) and iodine (1.25 g, 5 mmol) to the three-necked round-bottom flask to seal the reaction system. Then, add 250 mL of tetrahydrofuran to the three-necked round-bottom flask through a double-ended needle, and transfer 50 mL of a tetrahydrofuran solution of 2,4,6-triisopropylbromobenzene (1.0 mol / L) to the constant-pressure dropping funnel. The reaction apparatus was stirred at room temperature and heated to reflux with a hair dryer. After reflux was maintained for 10 minutes, a tetrahydrofuran solution of 2,4,6-triisopropylbenzene bromide was added dropwise. The reaction solution gradually turned grayish white. The remaining tetrahydrofuran solution of 2,4,6-triisopropylbenzene bromide was then added dropwise under stirring at room temperature. After the addition was completed, stirring was continued at room temperature for 1 hour, and then refluxed for another 1 hour.

[0166] 2) After the reaction is completed, add 50 mL (1.0 mol / L) of 2,4,6-tribromoiodobenzene in tetrahydrofuran solution to the constant pressure dropping funnel, heat the reaction bottle to reflux, and start to dropwise add 2,4,6-tribromoiodobenzene in tetrahydrofuran solution. The addition will be completed in about 1 hour, and the reflux reaction will continue for 12 hours.

[0167] 3) After the reaction was completed, 200 mL of saturated ammonium chloride was used to quench the reaction, and the mixture was transferred to a separatory funnel, the organic phase was collected, and the aqueous phase was washed with dichloromethane (3×100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The residue was distilled under reduced pressure at 160°C to remove residual 1,3,5-triisopropylbenzene. After there was no distillate in the system, the reaction system was cooled to room temperature, methanol was added, ultrasonic crystallization was performed, and the target compound C was obtained by filtration with a yield of 54% as a white solid. The purity analysis by HPLC was 90%.

[0168] Combining Comparative Examples 1 and 2, the creativity and beneficial effects of the technical solution of the present invention can be clearly understood. First, the present invention successfully reduces the amount of aryl Grignard reagent from 5 equivalents to 2.3 equivalents, effectively avoiding the use of high-value and dangerous aryl Grignard reagents, while avoiding the problem of separation of aryl compounds generated after quenching, that is, high-purity products can be obtained without vacuum distillation or chromatographic column purification. Secondly, the continuous synthesis process effectively avoids the threat of Grignard reagents that often exist in intermittent reactions, and can complete production tasks more flexibly, more efficiently, and more easily scaled up. Finally, the technical solution of the present invention significantly improves the yield of the product (such as the yield of compound A is increased from 76% to 92%, and the yield of compound C is increased from 54% to 92%), and the equipment cost and reagent cost are effectively controlled.

[0169] It can be seen from the above embodiments that the iodobenzene compounds of the continuous synthesis method of the m-terphenyl compounds of the present invention have a wide range of applications, and a series of m-terphenyl compounds can be obtained by changing the iodobenzene compounds and the Grignard reagent according to the needs, which has broad application prospects.

[0170] Although the embodiments of the present invention have been disclosed as above, they are not limited to the applications listed in the specification and the implementation modes. They can be fully applied to various fields suitable for the present invention. For those familiar with the art, additional modifications can be easily implemented. Therefore, without departing from the general concept defined by the claims and the scope of equivalents, the present invention is not limited to specific details.

Claims

1. A continuous synthesis method of m-terphenyl compounds, characterized in that: The following steps are involved: Step S1: using a tetrahydrofuran solution of an iodobenzene compound as feed liquid A and a tetrahydrofuran solution of isopropylmagnesium chloride·lithium chloride as feed liquid B; mixing feed liquid A and feed liquid B and performing a magnesium halogen exchange reaction to obtain a reaction liquid D; The concentration of the iodobenzene compound in the feed liquid A is 0.65-1.3 mol / L; the concentration of isopropylmagnesium chloride·lithium chloride in the feed liquid B is 1.3 mol / L; the molar ratio of the iodobenzene compound to isopropylmagnesium chloride·lithium chloride is 1:1-1.3; Step S2: using an aryl Grignard reagent solution as a feed solution C, mixing the feed solution C and the reaction solution D, and then sequentially performing a primary elimination reaction, a primary addition reaction, a secondary elimination reaction and a secondary addition reaction at 80-100° C. to obtain a reaction solution E; The concentration of the aromatic Grignard reagent solution is 0.5-2.0 mol / L; the molar ratio of the iodobenzene compound in step S1 to the aromatic Grignard reagent in step S2 is 1:2.1-2.5; Step S3: receiving and quenching the reaction solution E with a saturated aqueous solution of ammonium chloride, and then separating, drying, concentrating, and recrystallizing to obtain the target product, a m-terphenyl compound; Synthesis of m-terphenyl compounds using micro-reactors; The iodobenzene compound has a structure as shown in the following formula I; the aromatic Grignard reagent is ArMgX, X is chlorine or bromine; the intermediate product contained in the reaction solution D has a structure as shown in the following formula II; the intermediate product contained in the reaction solution E has a structure as shown in the following formula III; the target product m-terphenyl compound has a structure as shown in the following formula IV: Here, X is a chlorine atom or a bromine atom, and R is a hydrogen atom, a chlorine atom or a bromine atom.

2. The continuous synthesis method of a m-terphenyl compound according to claim 1, characterized in that: The aryl Grignard reagent solution in step S2 is a tetrahydrofuran or 2-methyl-tetrahydrofuran solution of the aryl Grignard reagent.

3. The continuous synthesis method of a m-terphenyl compound according to claim 1, characterized in that: The micro-reaction device comprises a first feed pump, a second feed pump, a third feed pump, a first mixer, a second mixer, a first microreactor, a second microreactor, a back pressure valve and a receiving device; wherein the first feed pump and the second feed pump are respectively connected to the first mixer by a pipeline, the first mixer is connected to the first microreactor by a pipeline, the third feed pump and the first microreactor are respectively connected to the second mixer by a pipeline, and the second mixer, the second microreactor, the back pressure valve and the receiving device are sequentially connected by a pipeline; The equipment is used to continuously synthesize terphenyl compounds. The specific process conditions are as follows: feed liquid A is fed by a first feed pump, and feed liquid B is fed by a second feed pump, so that feed liquid A and feed liquid B are simultaneously pumped into a first microreactor through a first mixer to perform a magnesium halogen exchange reaction to obtain a reaction liquid D; the reaction liquid D flows out of the first microreactor and enters a second mixer, while feed liquid C is fed by a third feed pump into the second mixer to mix with the reaction liquid D, and the obtained mixed solution continues to flow into the second microreactor, and the second microreactor is heated. The reaction liquid D undergoes a primary elimination reaction, the intermediate product 1 undergoes a primary addition reaction with part of the aryl Grignard reagent in the feed liquid C, the intermediate product 2 undergoes a secondary elimination reaction, and the intermediate product 3 undergoes a secondary addition reaction with the remaining aryl Grignard reagent in the feed liquid C, and finally obtains the reaction liquid E; the reaction liquid E flowing out through the back pressure valve is received and quenched by a receiving device filled with a saturated ammonium chloride aqueous solution, and then the target product m-terphenyl compound is obtained after separation, drying, concentration and recrystallization; The intermediate product 1 has a structure as shown in the following formula V, the intermediate product 2 has a structure as shown in the following formula VI, and the intermediate product 3 has a structure as shown in the following formula VII, wherein X is a chlorine atom or a bromine atom, and R is a hydrogen atom, a chlorine atom or a bromine atom: 。 4. The continuous synthesis method of a m-terphenyl compound according to claim 3, characterized in that: The retention time of the reaction solution D in the first microreactor is 40-120 seconds; the reaction temperature of the reaction solution D in the first microreactor is -10-25°C.

5. The continuous synthesis method of a m-terphenyl compound according to claim 3, characterized in that: The retention time of the reaction solution E in the second microreactor is 8-16 minutes.

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