Continuous synthesis method and device of 1, 2-disubstituted aromatic hydrocarbon compound

Abstract

The invention belongs to the technical field of organic synthesis and continuous flow synthesis, and discloses a continuous synthesis method and device of a 1, 2-disubstituted aromatic hydrocarbon compound. On the basis of a continuous flow technology, the advantages of three-pass and one-reaction of the continuous flow technology in the chemical reaction process are fully utilized, a magnesium halide exchange reaction, an elimination reaction, an addition reaction and a nucleophilic substitution reaction involved in the reaction are distinguished and are sequentially carried out under corresponding reaction conditions and in the reactor, the selectivity and the yield of the reaction are greatly improved, and the method is suitable for industrial production. The generation amount and types of wastes are reduced, the loss of reagents is reduced, and the post-treatment process is simplified. According to the method, the magnesium halide exchange reaction is performed by selecting isopropyl magnesium chloride and lithium chloride, so that the stability, safety and controllability of the reaction are improved, the method has good compatibility and expansibility, the preparation of various products can be met, and the product yield can reach a good level or above. The method has the advantages of low cost, simplicity and convenience in operation, high space-time efficiency, low emission of three wastes and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and continuous flow synthesis, and specifically relates to a continuous synthesis method and device for 1,2-disubstituted aromatic compounds. Background Art

[0002] 1,2-disubstituted aromatic compounds have diverse spatial structures, charge characteristics, reactivity, physical parameters, etc., and are widely present in the fields of natural products, chemical drugs, ligands, optoelectronic materials, etc. So far, many methods for the synthesis of 1,2-disubstituted aromatic compounds have been developed. Among them, active benzyne intermediates have been widely studied in aromatic functionalization reactions due to their high reactivity. The main preparation methods of aromatic alkynes include removing two adjacent atoms or substituents from halogenated aromatic hydrocarbons and ortho-dihalogenated aromatic hydrocarbon precursors. This method usually requires the use of strong bases (such as NaNH2), hindered lithium amides (LDA, LiTMP, LDAM, etc.), Grignard reagents or alkyl lithium reagents. However, it is difficult to control the formation and rapid decomposition of highly reactive aromatic alkynes under such reaction conditions, and there are complex side reactions. In addition, the storage and use of alkyl lithium reagents are relatively strict and need to be carried out at ultra-low temperatures. The participation of traditional Grignard reagents requires high-temperature reflux for halogen magnesium exchange, and the reaction conditions are harsh. Another is the method developed by Kobayashi et al. using o-silyl aryl triflate as an arylacene precursor. This scheme is widely used due to the controllable generation of aromatic species under mild reaction conditions. However, the high cost and cumbersome synthesis of o-silyl aryl triflate precursors limit their practical application, especially in industrial environments. Therefore, a process for preparing benzyne intermediates with cheap and readily available reaction precursors, safe and stable reaction processes, and simple and green post-reaction treatment has important economic and academic value. The preparation method of benzyne intermediates is shown in the following formula:

[0003] .

[0004] Ortho-substituted aryl Grignard reagents are effective precursors for the preparation of 1,2-disubstituted aromatic compounds. As Grignard reagents, they can undergo nucleophilic substitution reactions with aldehydes, ketones, amides, esters, isocyanates, anhydrides, Weinreb amides, halogens, cyano groups, chlorophosphine, etc., to obtain products with diverse functional groups. As an emerging green technology, continuous flow technology can strengthen and improve the "three-pass and one-reverse" reaction process. Compared with intermittent reactions, the control of continuous flow synthesis conditions is more precise, which can ensure that the reaction materials reach a certain residence time in the microreactor, thereby obtaining the expected reaction intermediates. Therefore, with continuous flow technology as the link, the efficient preparation of benzyne intermediates, the synthesis of ortho-substituted aryl Grignard reagents and nucleophilic substitution reactions are combined, and while improving each reaction, the synthesis of high-value ortho-disubstituted aromatic compounds is completed. The entire scheme has broad economic and academic value. Summary of the invention

[0005] In order to solve the shortcomings and deficiencies of the above-mentioned prior art such as complex reaction process, poor reaction control, harsh reaction conditions, long process flow, complex handling 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 1,2-disubstituted aromatic compounds, which realizes the economical, green, safe and efficient full-continuous preparation of such compounds.

[0006] Another object of the present invention is to provide a device for implementing the above-mentioned continuous synthesis method.

[0007] To achieve the above object, the present invention adopts the following technical solution:

[0008] A continuous synthesis method for a 1,2-disubstituted aromatic compound comprises the following steps:

[0009] Step S1: using a tetrahydrofuran solution of substrate 1,2-dihalobenzene as feed liquid A, and using a tetrahydrofuran solution of isopropylmagnesium chloride·lithium chloride as feed liquid B; mixing feed liquid A and feed liquid B, and then performing a magnesium-halide exchange reaction to obtain a reaction liquid E;

[0010] The concentration of the substrate 1,2-dihalobenzene in the feed solution A is 0.65-1.3 mol / L; the concentration of isopropylmagnesium chloride·lithium chloride in the feed solution B is 1.3 mol / L; the molar ratio of the substrate 1,2-dihalobenzene to isopropylmagnesium chloride·lithium chloride is 1:1-1.3;

[0011] Step S2: subjecting the reaction solution E to an elimination reaction to obtain a reaction solution F containing a benzylene intermediate;

[0012] Step S3: using a Grignard reagent solution as a feed solution C, mixing the feed solution C and the reaction solution F, and then performing an addition reaction to obtain a reaction solution G containing an ortho-substituted aryl Grignard reagent;

[0013] The concentration of the Grignard reagent solution is 0.25-2.0 mol / L; the molar ratio of the substrate 1,2-dihalobenzene in step S1 to the Grignard reagent in step S3 is 1:1.1-1.3;

[0014] Step S4: using a solution containing an electrophilic reagent as a feed solution D, mixing the feed solution D with a reaction solution G, and then performing a nucleophilic substitution reaction to obtain a reaction solution H containing a target product, a 1,2-disubstituted aromatic compound;

[0015] The concentration of the electrophilic reagent solution is 0.5 or 1.0 mol / L; the molar ratio of the substrate 1,2-dihalogenated benzene in step S1 to the electrophilic reagent in step S4 is 1:1.2-2.0;

[0016] Step S5: receiving and quenching the reaction solution H with a saturated aqueous ammonium chloride solution, and then obtaining the target product 1,2-disubstituted aromatic compound after separation, drying, concentration and purification.

[0017] The above-mentioned continuous synthesis method has the following equations: the 1,2-dihalogenated benzene has a structure shown in the following formula I; the intermediate product contained in the reaction solution E has a structure shown in the following formula II; the intermediate product contained in the reaction solution F has a structure shown in the following formula III; the intermediate contained in the reaction solution G has a structure shown in the following formula IV; the target product 1,2-disubstituted aromatic compound has a structure shown in the following formula V:

[0018]

[0019] Wherein X1 is iodine or bromine, X2 is bromine or chlorine; R1 and R2 are the same or different substituents, including hydrogen atoms or alkyl groups; X is bromine or chlorine; R3 is an aryl group, a cycloalkyl group or a chain alkyl group; R4 is a substituent produced by a nucleophilic substitution reaction of an aldehyde, a ketone, an amide, an ester, an isocyanate, an anhydride, a Weinreb amide, a halogen, a cyano group or a chlorophosphine group.

[0020] In step S3, the Grignard reagent is an aryl or alkyl Grignard reagent with a chemical formula of R3MgX, where R3 is an aryl, cycloalkyl or chain alkyl group, and X is chlorine or bromine; and the Grignard reagent solution is a Grignard reagent solution in tetrahydrofuran or 2-methyl-tetrahydrofuran.

[0021] In step S4, the electrophilic reagent is a chemical reagent that reacts with a Grignard reagent, including aldehydes, ketones, amides, esters, isocyanates, anhydrides, Weinreb amides, halogens, cyano groups or chlorophosphine; and the electrophilic reagent-containing solution is a tetrahydrofuran or 2-methyltetrahydrofuran solution of the electrophilic reagent.

[0022] A device for realizing the continuous synthesis method of the above-mentioned 1,2-disubstituted aromatic compound, the device comprises a first feed pump, a second feed pump, a third feed pump, a fourth feed pump, a first mixer, a second mixer, a third mixer, a first microreactor, a second microreactor, a third microreactor, a fourth 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 third feed pump and the second mixer are connected by a pipeline, the fourth feed pump and the third mixer are connected by a pipeline, and the first mixer, the first microreactor, the second microreactor, the second mixer, the third microreactor, the third mixer, the fourth microreactor, the back pressure valve and the receiving device are sequentially connected by a pipeline.

[0023] The device is used to continuously synthesize 1,2-disubstituted aromatic compounds, and 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 E; the reaction liquid E continues to flow into the second microreactor to perform an elimination reaction to obtain a reaction liquid F containing a benzylene intermediate; feed liquid C is fed by a third feed pump, so that feed liquid C and reaction liquid F are simultaneously pumped into the second microreactor through the second mixer; In the three microreactors, an addition reaction is carried out to obtain a reaction liquid G containing an ortho-substituted aromatic Grignard reagent; a feed liquid D is fed by a fourth feed pump, and the feed liquid D and the reaction liquid G are mixed in a third mixer and then enter the fourth microreactor to carry out a nucleophilic substitution reaction to obtain a reaction liquid H containing a target product 1,2-disubstituted aromatic compound; a receiving device filled with a saturated ammonium chloride aqueous solution is used to receive and quench the reaction liquid H flowing out through a back pressure valve, and then the target product 1,2-disubstituted aromatic compound is obtained after liquid separation, drying, concentration and purification.

[0024] The retention time of the reaction solution E in the first microreactor is 20-80 seconds; the reaction temperature (T1) of the reaction solution E in the first microreactor is -20-25°C.

[0025] The retention time of the reaction solution F in the second microreactor is 2-5 minutes; the reaction temperature (T2) of the reaction solution F in the second microreactor is 70-100°C.

[0026] The retention time of the reaction liquid G in the third microreactor is 20-60 seconds; the reaction temperature (T3) of the reaction liquid G in the third microreactor is 25-60°C.

[0027] The retention time of the reaction solution H in the fourth microreactor is 2-6 minutes; the reaction temperature (T4) of the reaction solution H in the fourth microreactor is 25-60°C.

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

[0029] .

[0030] Wherein X1 is iodine or bromine, X2 is bromine or chlorine; R1 and R2 are the same or different substituents, including hydrogen atoms or alkyl groups; X is bromine or chlorine; R3 is an aryl group, a cycloalkyl group or a chain alkyl group; R4 is a substituent produced by a nucleophilic substitution reaction of an aldehyde, a ketone, an amide, an ester, an isocyanate, an anhydride, a Weinreb amide, a halogen, a cyano group or a chlorophosphine group.

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

[0032] 1. The present invention is based on continuous flow technology, making full use of its advantage of "three transmissions and one reaction" in the chemical reaction process, distinguishing the lithium halogen exchange reaction, elimination reaction, addition reaction and nucleophilic substitution reaction involved in the reaction, so that they occur in sequence under corresponding reaction conditions and reactors, greatly improving the selectivity and yield of the reaction, reducing the amount and type of waste generated, reducing the loss of reagents, simplifying the post-processing process, so that the technical solution has the advantages of low cost, simple operation, high time and space efficiency, and low emission of three wastes.

[0033] 2. In the present invention, isopropylmagnesium chloride·lithium chloride is selected to carry out the magnesium halogen exchange reaction, so that the magnesium halogen exchange reaction is carried out under relatively mild conditions, which improves the stability, safety and controllability of the reaction, and provides favorable guarantees for its application in scale-up production. In addition, the use of isopropylmagnesium chloride·lithium chloride avoids the need for 1 equivalent of Grignard reagent. For reactions that require the use of complex and expensive Grignard reagents, while simplifying the post-processing operation, the economic cost brought by the aromatic Grignard reagent is effectively reduced.

[0034] 3. This technical solution has good compatibility and scalability, can meet the preparation of a variety of products, and the product yield can reach a good to excellent level. The continuous flow technology used has high operational safety and a large production capacity flexibility range. It is a green, environmentally friendly, economical and efficient method for producing ortho-disubstituted aromatic compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1Schematic diagram of the device for realizing the continuous synthesis method of 1,2-disubstituted aromatic compounds of the present invention, wherein 1 is a first feed pump, 2 is a second feed pump, 3 is a third feed pump, 4 is a fourth feed pump, 5 is a first mixer, 6 is a second mixer, 7 is a third mixer, 8 is a first microreactor, 9 is a second microreactor, 10 is a third microreactor, 11 is a fourth microreactor, 12 is a back pressure valve, 13 is a receiving device, and 14 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 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 1,2-disubstituted aromatic 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 fourth feed pump 4, a first mixer 5, a second mixer 6, a third mixer 7, a first microreactor 8, a second microreactor 9, a third microreactor 10, a fourth microreactor 11, a back pressure valve 12 and a receiving device 13, wherein the first feed pump 1 and the second feed pump 2 are respectively connected to the first mixer 5 by a pipeline, the third feed pump 3 and the second mixer 6 are connected by a pipeline, the fourth feed pump 4 and the third mixer 7 are connected by a pipeline, and the first mixer 5, the first microreactor 8, the second microreactor 9, the second mixer 6, the third microreactor 10, the third mixer 7, the fourth microreactor 11, the back pressure valve 12 and the receiving device 13 are sequentially connected by pipelines.

[0044] The device is used to continuously synthesize 1,2-disubstituted aromatic compounds, and 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 E; the reaction liquid E continues to flow into the second microreactor to perform an elimination reaction to obtain a reaction liquid F containing a benzylene intermediate; feed liquid C is fed by a third feed pump, so that feed liquid C and reaction liquid F are simultaneously pumped into the second microreactor through the second mixer; In the three microreactors, an addition reaction is carried out to obtain a reaction liquid G containing an ortho-substituted aromatic Grignard reagent; a feed liquid D is fed by a fourth feed pump, and the feed liquid D and the reaction liquid G are mixed in a third mixer and then enter the fourth microreactor to carry out a nucleophilic substitution reaction to obtain a reaction liquid H containing a target product 1,2-disubstituted aromatic compound; a receiving device filled with a saturated ammonium chloride aqueous solution is used to receive and quench the reaction liquid H flowing out through a back pressure valve, and then the target product 1,2-disubstituted aromatic compound is obtained after liquid separation, drying, concentration and purification.

[0045] The following examples 1-20 studied the effects of reaction temperature, retention time, molar ratio of feed, and feed liquid concentration on the reaction effect through the synthesis of 2-diphenylphosphine-biphenyl. 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 molar ratio of feed of magnesium halogen exchange reaction in Examples 1, 4-5 was different; the substrate feed concentration in Examples 1 and 6 was different; Example 1, 7-8 used different retention times and reaction temperatures for elimination reaction, i.e., the reaction occurred in the second microreactor; Example 1, 9-10 used different retention times and reaction temperatures for addition reaction, i.e., the reaction occurred in the third microreactor; Example 1, 11-12 used different amounts of Grignard reagent; Example 1, 13-15 used different feed liquid concentrations of Grignard reagent; Example 1, 16-17 used different retention times and reaction temperatures for nucleophilic substitution reaction, i.e., the reaction occurred in the fourth microreactor; Example 1, 18-19 used different amounts of electrophilic reagent; Example 1 and 20 used different concentrations of electrophilic reagent.

[0046] The synthetic reaction formula of 2-diphenylphosphine-biphenyl in Example 1-20 is as follows:

[0047] .

[0048] Example 1

[0049] (1) Preparation of feed liquid:

[0050] Feed liquid A: Weigh 46 g (162.5 mmol) of substrate o-bromoiodobenzene and add it to a three-necked round-bottom flask. Dissolve it in tetrahydrofuran and make it up to 250 mL under nitrogen atmosphere to obtain feed liquid A with a concentration of 0.65 mol / L.

[0051] Feed solution B: commercial isopropylmagnesium chloride·lithium chloride solution in tetrahydrofuran (1.3 mol / L);

[0052] Feed liquid C: phenylmagnesium chloride tetrahydrofuran solution (1 mol / L);

[0053] Feed liquid D: Weigh 36 g (162.5 mmol) of diphenylphosphine chloride and add it to a three-necked round-bottom flask. Under a nitrogen atmosphere, dissolve it with tetrahydrofuran and make the volume to 250 mL to obtain a feed liquid D with a concentration of 0.65 mol / L.

[0054] (2) Pump flow rate parameter setting:

[0055] The flow rate of the first feed pump pumping feed liquid A is 2 mL / min;

[0056] The flow rate of the second feed pump pumping feed liquid B is 1.1 mL / min;

[0057] The flow rate of the third feed pump for pumping feed liquid C is 1.5 mL / min;

[0058] The flow rate of the fourth feed pump for pumping feed liquid D is 2 mL / min.

[0059] (3) Microreactor parameter setting:

[0060] The retention volume of the first microreactor was 2.6 mL, the reaction temperature T1 was 0 °C, and the residence time was 50 s;

[0061] The retention volume of the second microreactor was 10.9 mL, the reaction temperature T2 was 80 °C, and the residence time was 3.5 min;

[0062] The retention volume of the third microreactor was 4.6 mL, the reaction temperature T3 was 25 °C, and the residence time was 60 s;

[0063] The retention volume of the fourth microreactor was 26.4 mL, the reaction temperature T4 was 45 °C, and the residence time was 4 min.

[0064] (4) Feeding molar ratio:

[0065] The molar ratio of substrate o-bromoiodobenzene to isopropylmagnesium chloride·lithium chloride is 1:1.1;

[0066] The molar ratio of substrate o-bromoiodobenzene to phenylmagnesium chloride is 1:1.15;

[0067] The molar ratio of substrate o-bromoiodobenzene to diphenylphosphine chloride is 1:1.5.

[0068] (5) Continuous synthesis process:

[0069] 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 E; the reaction liquid E continues to flow into a second microreactor for an elimination reaction to obtain a reaction liquid F containing a benzylene intermediate; feed liquid C is fed by a third feed pump, so that feed liquid C and reaction liquid F are simultaneously pumped into a third microreactor through a second mixer to perform an addition reaction to obtain a reaction liquid G containing an ortho-substituted aromatic Grignard reagent; feed liquid D is fed by a fourth feed pump, so that feed liquid D and reaction liquid G are mixed in the third mixer and then enter a fourth microreactor to perform a nucleophilic substitution reaction to obtain a reaction liquid H containing a target product 1,2-disubstituted aromatic compound; and a receiving device filled with a saturated aqueous ammonium chloride solution is used to receive and quench the reaction liquid H flowing out through a back pressure valve.

[0070] 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 filtered and recorded as product A. The yield was 85% and the purity of HPLC analysis was greater than 99%. The obtained product was characterized, and the data results were as follows:

[0071] 1 H NMR (400 MHz, DMSO-d6) δ 7.47 (td, J = 7.5, 1.4 Hz, 1H), 7.41-7.31(m, 8H), 7.29 (dd, J = 5.0, 1.9 Hz, 3H), 7.20-7.10 (m, 6H), 6.97 (dd, J =6.9, 4.6 Hz, 1H). 31 P NMR (162 MHz, DMSO-d6) δ -14.64. 13 C NMR (101 MHz, DMSO-d6) δ 141.72, 137.68, 137.56, 134.27, 133.83, 133.63, 130.65, 129.86 (d, J =4.0 Hz), 129.63, 129.20, 129.17, 129.10, 128.10, 127.66.

[0072] Example 2

[0073] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0074] The retention volume of the first microreactor was 4.2 mL, the reaction temperature was -20 °C, and the residence time was 80 s. The product 2-diphenylphosphine-biphenyl obtained in this example was a white solid product with a yield of 83% and a purity of more than 99% according to HPLC analysis.

[0075] Example 3

[0076] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0077] The retention volume of the first microreactor was 1.1 mL, the reaction temperature was 25° C., and the residence time was 20 s. The product 2-diphenylphosphine-biphenyl obtained in this example was a white solid product with a yield of 81% and a purity of greater than 99% according to HPLC analysis.

[0078] Example 4

[0079] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0080] 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 substrate o-bromoiodobenzene to isopropylmagnesium chloride·lithium chloride is 1: 1. The product 2-diphenylphosphine-biphenyl obtained in this embodiment is a white solid product with a yield of 76% and a purity of more than 99% according to HPLC analysis.

[0081] Example 5

[0082] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0083] 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 substrate o-bromoiodobenzene to isopropylmagnesium chloride·lithium chloride is 1:1.3. The product 2-diphenylphosphine-biphenyl obtained in this embodiment is a milky white solid product with a yield of 85% and a purity of 97% by HPLC analysis.

[0084] Example 6

[0085] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0086] The concentration of o-bromoiodobenzene 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 1.7 mL. The product 2-diphenylphosphine-biphenyl 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.

[0087] Example 7

[0088] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0089] The retention volume of the second microreactor was 6.2 mL, the reaction temperature T2 was 100° C., and the residence time was 2 min. The product 2-diphenylphosphine-biphenyl 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.

[0090] Example 8

[0091] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0092] The retention volume of the second microreactor was 15.6 mL, the reaction temperature T2 was 70° C., and the residence time was 5 min. The product 2-diphenylphosphine-biphenyl obtained in this example was a white solid product with a yield of 88% and a purity of more than 99% according to HPLC analysis.

[0093] Example 9

[0094] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0095] The retention volume of the third microreactor was 3.5 mL, the reaction temperature T3 was 50° C., and the residence time was 45 s. The product 2-diphenylphosphine-biphenyl obtained in this example was a white solid product with a yield of 85% and a purity of more than 99% according to HPLC analysis.

[0096] Example 10

[0097] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0098] The retention volume of the third microreactor was 1.5 mL, the reaction temperature T3 was 60° C., and the residence time was 20 s. The product 2-diphenylphosphine-biphenyl obtained in this example was a white solid product with a yield of 86% and a purity of greater than 99% according to HPLC analysis.

[0099] Embodiment 11

[0100] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0101] The flow rate of the third feed pump for pumping feed liquid C is 1.3 mL / min, that is, the molar ratio of substrate o-bromoiodobenzene to phenylmagnesium chloride is 1: 1. The product 2-diphenylphosphine-biphenyl obtained in this example is a white solid product with a yield of 76% and a purity of 98% according to HPLC analysis.

[0102] Example 12

[0103] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0104] The flow rate of the third feed pump for pumping feed liquid C is 1.7 mL / min, that is, the molar ratio of substrate o-bromoiodobenzene to phenylmagnesium chloride is 1:1.3. The product 2-diphenylphosphine-biphenyl obtained in this example is a white solid product with a yield of 90% and a purity of 98% by HPLC analysis.

[0105] Example 13

[0106] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0107] 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 3.0 mL / min, and the retention volume of the third microreactor is 6.1 mL. The product 2-diphenylphosphine-biphenyl obtained in this embodiment is a milky white solid product with a yield of 88% and a purity of greater than 99% by HPLC analysis.

[0108] Embodiment 14

[0109] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0110] 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 0.75 mL / min, and the retention volume of the third microreactor is 3.1 mL. The product 2-diphenylphosphine-biphenyl obtained in this example is a milky white solid product with a yield of 87% and a purity of greater than 99% by HPLC analysis.

[0111] Embodiment 15

[0112] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0113] The concentration of phenylmagnesium chloride in the feed liquid C is 0.25 mol / L, the flow rate of the third feed pump for pumping the feed liquid C is 6 mL / min, and the retention volume of the third microreactor is 9.1 mL. The product 2-diphenylphosphine-biphenyl obtained in this embodiment is a milky white solid product with a yield of 88% and a purity of greater than 99% by HPLC analysis.

[0114] Example 16

[0115] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0116] The retention volume of the fourth microreactor was 12.2 mL, the reaction temperature was 60° C., and the residence time was 2 min. The product 2-diphenylphosphine-biphenyl obtained in this example was a white solid product with a yield of 86% and a purity of more than 99% according to HPLC analysis.

[0117] Embodiment 17

[0118] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0119] The retention volume of the fourth microreactor was 36.6 mL, the reaction temperature was 25° C., and the residence time was 6 min. The product 2-diphenylphosphine-biphenyl obtained in this example was a white solid product with a yield of 88% and a purity of more than 99% according to HPLC analysis.

[0120] Embodiment 18

[0121] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0122] The flow rate of the fourth feed pump for pumping feed liquid D is 1.6 mL / min, that is, the molar ratio of substrate o-bromoiodobenzene to phenylmagnesium chloride is 1:1.2. The product 2-diphenylphosphine-biphenyl obtained in this example is a white solid product with a yield of 81% and a purity of 98% according to HPLC analysis.

[0123] Embodiment 19

[0124] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0125] The flow rate of the fourth feed pump for pumping feed liquid D is 2.6 mL / min, that is, the molar ratio of substrate o-bromoiodobenzene to phenylmagnesium chloride is 1:1.3. The product 2-diphenylphosphine-biphenyl obtained in this example is a white solid product with a yield of 90% and a purity of 98% by HPLC analysis.

[0126] Embodiment 20

[0127] The overall solution of this embodiment is basically the same as that of Embodiment 1, except that:

[0128] The concentration of diphenylmagnesium chloride in the feed liquid D is 0.5 mol / L, the flow rate of the third feed pump for pumping the feed liquid C is 2.6 mL / min, and the retention volume of the fourth microreactor is 30.4 mL. The product 2-diphenylphosphine-biphenyl obtained in this example is a milky white solid product with a yield of 88% and a purity of more than 99% by HPLC analysis.

[0129] The target product BK, i.e., a biphenylphosphine compound, was prepared by Examples 21-30. The operation of Examples 21-30 was basically the same as that of Example 1, except that the types of Grignard reagents and electrophilic reagents used were different, as shown in Table 1 below.

[0130] Table 1 Product yields of Examples 21-30

[0131]

[0132] Example 21 The structural formula of target product B:

[0133]

[0134] The target product B 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: 1H NMR (400 MHz, Methylene Chloride-d2) δ 7.24 (d, J = 7.7 Hz,1H), 7.18 (d, J = 3.9 Hz, 7H), 7.13-7.08 (m, 5H), 7.01 (d, J = 6.4 Hz, 2H), 6.94 (dd, J = 7.6, 3.7 Hz, 1H), 6.68 (d, J = 8.6 Hz, 2H), 3.65 (s, 3H). 31 PNMR (162 MHz, Methylene Chloride-d2) δ -13.72. 13 C NMR (101 MHz, MethyleneChloride-d2) δ 159.01, 148.11 (d, J = 29.0 Hz), 138.04 (d, J = 12.4 Hz), 135.89 (d, J = 14.0 Hz), 134.35, 133.96, 133.76, 130.97 (d, J = 4.0 Hz), 130.37 (d, J = 4.8 Hz), 128.85, 128.53, 128.46, 127.18, 112.98, 55.25.

[0135] Example 22 The structural formula of target product C:

[0136]

[0137] The target product C 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, DMSO-d6) δ 7.46 (td, J = 7.5, 1.4 Hz, 1H), 7.42-7.28 (m, 8H), 7.20 (dd, J = 7.8, 5.5 Hz, 2H), 7.17-7.05 (m, 6H), 6.96 (ddd, J= 7.7, 3.8, 1.3 Hz, 1H). 31 P NMR (162 MHz, DMSO-d6) δ -14.31. 13C NMR (101 MHz, DMSO-d6) δ 161.94 (d, J = 244.0 Hz), 146.93 (d, J = 27.9 Hz), 137.96 (dd, J =5.9, 3.3 Hz), 137.26 (d, J = 12.4 Hz), 135.70 (d, J = 15.0 Hz), 134.07,133.80 (d, J = 19.9 Hz), 131.82 (dd, J = 8.2, 4.1 Hz), 130.67 (d, J = 4.6Hz), 129.63, 129.29, 129.15 (d, J = 6.7 Hz), 128.25, 114.92 (d, J = 21.4 Hz).

[0138] Example 23 The structural formula of target product D:

[0139]

[0140] The target product D 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, DMSO-d6) δ 7.46 (td, J = 7.5, 1.4 Hz, 1H), 7.41-7.27 (m, 10H), 7.19 (dd, J = 8.4, 1.1 Hz, 2H), 7.17-7.09 (m, 4H), 6.99 (ddd,J = 7.7, 3.8, 1.3 Hz, 1H). 31 P NMR (162 MHz, DMSO-d6) δ -14.49. 13 C NMR (101MHz, DMSO-d6) δ 146.73 (d, J = 28.0 Hz), 140.45 (d, J = 5.9 Hz), 137.20 (d, J= 12.4 Hz), 135.55 (d, J = 15.2 Hz), 134.19, 133.78 (d, J = 20.0 Hz), 132.63,131.66 (d, J = 4.2 Hz), 130.54 (d, J = 4.7 Hz), 129.70, 129.30, 129.15 (d, J= 6.7 Hz), 128.43, 128.09.

[0141] Example 24 The structural formula of target product E:

[0142]

[0143] The target product E 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, DMSO-d6) δ 7.62 (dt, J = 5.0, 2.9 Hz, 1H), 7.42-7.39 (m, 2H), 7.36 (d, J = 7.6 Hz, 2H), 7.33-7.28 (m, 1H), 7.23 (dd, J = 8.5,4.9 Hz, 3H), 1.83 (t, J = 10.6 Hz, 2H), 1.60 (t, J = 5.6 Hz, 8H), 1.47 (d, J= 13.0 Hz, 2H), 1.25-1.05 (m, 6H), 1.02-0.88 (m, 4H). 31 P NMR (162 MHz, DMSO-d6) δ -14.11. 13 C NMR (101 MHz, DMSO-d6) δ 150.35 (d, J = 28.7 Hz), 142.86 (d, J = 6.0 Hz), 133.32 (d, J = 3.2 Hz), 130.85 (d, J = 4.5 Hz), 130.43 (d, J =5.1 Hz), 128.96, 127.80, 127.24, 126.93, 34.65 (d, J = 15.3 Hz), 30.69 (d, J= 18.0 Hz), 29.53 (d, J = 9.3 Hz), 27.02, 26.66 (d, J = 46.3 Hz).

[0144] Example 25 The structural formula of the target product F:

[0145]

[0146] The target product F 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: 1H NMR (400 MHz, C6D6) δ 7.46-7.40 (m,1H), 7.24-7.06 (m, 5H), 2.86(septet, J = 6.9 Hz, 1H), 2.71 (septet, J = 6.9 Hz, 2H), 1.92-1.50(m, 12H), 1.42 (d, J = 6.9 Hz, 6H), 1.34 (d, J = 6.9 Hz, 2H), 1.30-1.02 (m, 12H), 1.12 (d, J = 6.9Hz, 6H). 31 P NMR (162 MHz, C6D6) δ -11.3. 13 C NMR (101 MHz, C6D6) δ148.71, 148.62, 148.34,147.01, 146.99, 137.86, 137.78, 137.60, 137.58,132.92, 132.88, 132.32, 132.26, 128.27, 127.09, 121.06, 35.47, 35.38, 35.19,32.43, 31.96, 31.68, 31.66, 30.33, 30.12, 28.60, 28.45, 28.37, 28.28, 27.49,26.92, 25.01, 23.92, 23.90.

[0147] Example 26 The structural formula of the target product G is:

[0148]

[0149] 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: 1 H NMR (600 MHz, Chloroform-d) δ 7.49 (d, J = 6.0 Hz, 1H), 7.30 (t, J = 6.2 Hz,1H) 7.27-7.22 (m, 2H), 7.12-7.09 (m, 1H), 6.52 (d, J = 7.6 Hz,2H), 3.60 (s, 3H), 1.70-1.63 (m,2H), 1.62-1.51 (m, 10H), 1.19- 1.01 (m, 10H). 31 P NMR (81 MHz, Chloroform-d) δ –9.7.13 C NMR (151 MHz, Chloroform-d) δ157.52, 143.01,142.85, 136.07, 135.84, 132.43, 131.01, 130.96, 128.85,128.32, 126.23, 119.99, 55.30, 34.02, 33.95, 30.01, 29.93,29.16, 29.02,27.65, 27.58, 27.44, 27.35, 26.87, 26.74, 26.65, 26.07, 25.98, 25.89.

[0150] Example 27 The structural formula of the target product H:

[0151]

[0152] The yield of the target product H was 84%, 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 7.80-7.74 (m, 1H), 7.40-7.20 (m,4H), 7.00-6.90 (m, 3H), 2.44 (s, 6H), 1.26 (d, 9H, J = 11.3 Hz), 0.90 (d, 9H,J = 33.0 Hz). 31 P NMR (162 MHz, Chloroform-d) δ 25.6. 13 C NMR (101 MHz, Chloroform-d) δ 151.62 (d, J = 2.4 Hz), 150.13 (d, J = 32.7 Hz), 137.29 (d, J= 7.6 Hz), 136.92 (d, J = 15.2 Hz), 135.64(d, J = 3.5 Hz), 132.96, 131.17 (d,J = 7.1 Hz), 128.8 9(d, J = 1.2 Hz), 128.02, 125.36, 121.06, 117.67, 43.59,33.50 (d, J = 24.5 Hz), 31.73 (d, J = 16.1 Hz), 31.66 (d, J = 27.8 Hz), 30.22 (d, J = 15.2 Hz).

[0153] Example 28 The structural formula of the target product I:

[0154]

[0155] The target product I had a yield of 85%, a white solid, and a purity of greater than 99% according to HPLC. The obtained product was characterized, and the results were as follows: 1 H NMR (400 MHz, C6D6) δ 7.52 (d, J= 7.6 Hz, 1H), 7.30-7.14 (m,4H), 6.49 (d, J= 8.3 Hz, 2H), 4.21 (d, J= 6.0 Hz, 2H), 1.93-1.62 (m, 12H), 1.41-1.14 (m, 10H), 1.12 (d, J= 6.0 Hz, 6H), 0.92 (d, J= 6.0 Hz, 6H). 31 P NMR (162 MHz, C6D6) δ -8.87. 13 C NMR (101 MHz, C6D6) δ 157.05, 144.74, 144.47,137.82, 137.62, 132.46, 132.35, 131.92, 131.90, 126.45, 123.94, 123.91,106.64, 70.32, 35.21, 35.02, 30.90, 30.80, 30.75, 30.65, 28.01, 28.01, 27.93,27.37, 22.65, 22.37.

[0156] Example 29 The structural formula of target product J:

[0157]

[0158] The target product J has a yield of 79%, 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 7.86 (d, J = 7.4 Hz, 1H), 7.37-7.24 (m, 5H), 7.21 (d, J = 7.4 Hz, 3H), 1.08 (s, 18H). 31 P NMR (162 MHz, Chloroform-d) δ 20.23-15.57 (m). 13C NMR (101 MHz, Chloroform-d) δ 150.36,150.04, 142.78 (d, J = 7.2 Hz), 134.27 (d, J = 3.2 Hz), 129.55, 129.50 (d, J= 2.0 Hz), 127.33, 126.07, 125.34, 124.71, 31.69 (d,J = 24.9 Hz), 29.68 (d,J = 15.4 Hz).

[0159] Example 30 The structural formula of the target product 74 is:

[0160]

[0161] 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: 1 H NMR (400 MHz, C6D6) δ 7.83-7.73 (m, 1H), 7.32-7.24 (m,1H), 7.15-7.04 (m, 4H), 2.87-2.72 (m, 3H), 1.35 (d, J = 6.9 Hz, 6H), 1.21 (d, J =6.9 Hz, 6H), 1.12 (d, J = 11.1 Hz, 18H), 1.07 (d, J = 6.9 Hz, 6H). 31 P NMR (162MHz, C6D6) δ 21.42. 13 C NMR (101 MHz, C6D6) δ 149.73, 149.28, 148.73, 147.20,147.19, 138.22, 138.09, 137.95, 137.82, 136.69,136.66, 133.24, 133.16,128.67, 128.25, 126.22, 121.19, 35.24, 33.67, 33.34, 31.85, 31.81, 31.79,31.60, 27.42, 25.01, 23.65, 23.62.

[0162] The target product LS, i.e., ortho-functionalized biphenyl compounds, was prepared by using Examples 31-42. The operations of Examples 31-42 were basically the same as those of Example 1, except that different types of electrophilic reagents were used. See Table 2 for details.

[0163] Table 2 Product yields of Examples 31-42

[0164]

[0165] Example 31 The structural formula of the target product L:

[0166]

[0167] The target product L has a yield of 89%, a white solid, and a purity of more than 99% according to HPLC. The obtained product was characterized, and the results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 7.59 (dd, J = 7.8, 1.4 Hz, 1H), 7.45(t, J = 7.2 Hz, 2H), 7.42-7.35 (m, 2H), 7.33-7.26 (m, 3H), 7.13 (dd, J = 7.6,1.4 Hz, 1H), 5.02 (d, J = 3.9 Hz, 1H), 4.49 (s, 1H), 1.56-1.44 (m, 2H), 0.66(t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 143.85, 141.45, 140.41,129.75, 129.60, 128.59, 127.89, 127.36, 126.90, 126.68, 70.17, 32.12, 10.89.

[0168] Example 32 The structural formula of the target product M:

[0169]

[0170] The target product M has a yield of 87%, 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, DMSO-d6) δ 7.60 (dd, J = 7.8, 1.5 Hz, 1H), 7.47-7.39 (m, 2H), 7.38-7.31 (m, 4H), 7.28 (td, J = 7.4, 1.5 Hz, 1H), 7.09 (dd, J= 7.6, 1.5 Hz, 1H), 5.17 (d, J = 3.8 Hz, 1H), 4.68 (d, J = 3.9 Hz, 1H), 0.60(s, 9H). 13C NMR (101 MHz, DMSO-d6) δ 142.55, 141.75, 141.35, 130.01, 129.83,128.75, 128.54, 127.10, 126.94, 126.78, 74.93, 36.64, 26.58.

[0171] Example 33 The structural formula of the target product N:

[0172]

[0173] The yield of the target product N was 78%, 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, DMSO-d6) δ 7.49 (d, J = 7.7 Hz, 1H), 7.43 (d, J =8.2 Hz, 2H), 7.33 (d, J = 6.6 Hz, 3H), 7.23-7.11 (m, 5H), 7.04 (d, J = 7.7Hz, 2H), 5.82 (d, J = 4.3 Hz, 1H), 5.76 (d, J = 4.3 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 145.82, 142.96, 141.24, 140.82, 129.91, 129.67, 128.67, 128.33,128.08, 128.04, 127.57, 127.30, 126.94, 126.55, 70.68.

[0174] Example 34 The structural formula of the target product O is:

[0175]

[0176] The yield of the target product O was 82%, in the form of a colorless oil, and the HPLC purity analysis was greater than 99%. The obtained product was characterized, and the results were as follows: 1H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J = 8.1 Hz, 1H), 7.37-7.31(m, 4H), 7.27-7.22 (m, 2H), 7.20 (td, J = 7.4, 1.3 Hz, 1H), 6.92 (dd, J =7.5, 1.5 Hz, 1H), 4.45 (s, 1H), 1.61-1.39 (m, 8H), 1.24 (q, J = 3.8 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 148.09, 144.94, 140.73, 132.29, 130.03, 127.61,127.45, 126.96 (d, J = 7.7 Hz), 126.00, 73.34, 38.39, 25.51, 22.21.

[0177] The structural formula of the target product P in Examples 35-36 is:

[0178]

[0179] The target product P has a yield of 80% and 83%, a white solid, and a HPLC purity analysis of more than 99%. The obtained product was characterized, and the results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 9.99 (s, 1H), 8.03 (dd, J =7.8, 1.4 Hz, 1H), 7.65 (td, J = 7.5, 1.5 Hz, 1H), 7.48 (dt, J = 14.6, 7.6 Hz, 5H), 7.39 (dd, J = 7.6, 1.8 Hz, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 192.51,146.00, 137.77, 133.73, 133.58, 130.79, 130.12, 128.44, 128.14, 127.80,127.58.

[0180] The structural formula of the target product Q in Examples 37-40 is:

[0181]

[0182] The target product Q has a yield of 80% and 83%, a white solid, and a purity of more than 99% according to HPLC. The obtained product was characterized, and the results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 7.59 (t, J = 7.5 Hz, 2H), 7.44 (ddt, J = 19.7, 11.4, 7.5 Hz, 5H), 7.31 (d, J = 6.6 Hz, 2H), 2.12 (s, 3H). 13 CNMR (101 MHz, DMSO-d6) δ 203.84, 140.86, 140.32, 131.30, 130.78, 129.09, 129.07, 128.17, 128.12, 127.95, 30.74.

[0183] Example 41 The structural formula of the target product R:

[0184]

[0185] The target product R has a yield of 80% and 83%, a white solid, and a purity of more than 99% according to HPLC. The obtained product was characterized, and the results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 7.80-7.69 (m, 2H), 7.56 (td, J =7.6, 1.2 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 8.6 Hz, 2H), 7.02(d, J = 8.7 Hz, 2H), 3.81 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 189.43,163.03, 159.97, 142.93, 134.32, 133.68, 131.46, 131.11, 130.59, 130.31,127.85, 114.62, 55.77.

[0186] Example 42 The structural formula of the target product S is:

[0187]

[0188] The yield of the target product S was 89%, and the product was a white solid. The HPLC purity analysis was greater than 99%. The obtained product was characterized, and the results were as follows: 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.61-7.55 (m, 2H), 7.52-7.40 (m, 8H), 7.36 (t, J = 7.4 Hz, 2H), 7.29 (t, J = 7.2 Hz, 1H). 13 C NMR (101MHz, DMSO-d6) δ 168.40, 140.39, 139.73, 138.89, 137.28, 131.89, 130.47,130.40, 128.76, 128.74, 128.26, 127.79, 127.72, 121.90, 115.60.

[0189] The target product TV, i.e., an ortho-substituted benzamide compound, was prepared by Examples 43-45. The operation of Examples 43-45 was basically the same as that of Example 1, except that different types of Grignard reagents and electrophilic reagents were used. See Table 3 for details.

[0190] Table 3 Product yields of Examples 43-45

[0191]

[0192] Example 43 The structural formula of the target product T:

[0193]

[0194] The target product T 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, DMSO-d6) δ 10.76 (s, 1H), 7.60-7.54 (m, 2H), 7.52-7.48 (m, 2H), 7.39 (dd, J = 8.8, 3.3 Hz, 4H), 3.92 (d, J = 6.2 Hz, 2H), 1.82-1.74 (m, 1H), 0.72 (d, J = 6.7 Hz, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 154.77,151.41, 137.33, 137.00, 132.77 (d, J = 5.0 Hz), 130.72, 129.32, 129.22,128.00, 121.65, 73.02, 27.57, 18.96.

[0195] Example 44 The structural formula of the target product U:

[0196]

[0197] The target product U 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, DMSO-d6) δ 10.46 (s, 1H), 7.78 (d, J = 8.9 Hz, 2H), 7.45-7.38 (m, 4H), 7.34-7.30 (m, 2H), 2.78-2.68 (m, 2H), 1.61-1.48 (m, 2H),1.33-1.25 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ168.57, 140.59, 138.72, 137.33, 130.26, 130.14, 129.07, 127.69, 127.56,126.14, 121.61, 33.61, 32.66, 22.40, 14.18.

[0198] Example 45 The structural formula of the target product V is:

[0199]

[0200] The target product V had a yield of 87%, a white solid, and a purity of greater than 99% by HPLC. The obtained product was characterized, and the results were as follows: 1 H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 7.60-7.54 (m, 2H), 7.52-7.48 (m, 2H), 7.39 (dd, J = 8.8, 3.3 Hz, 4H), 2.79 (m, 1H), 1.93-1.63 (m,8H). 13 C NMR (101 MHz, DMSO-d6) δ 154.77, 151.41, 137.33, 137.00, 132.77 (d, J= 5.0 Hz), 130.72, 129.32, 129.22, 128.00, 121.65, 73.02, 27.57, 18.96.

[0201] The target products A and XZ were prepared by Examples 46-51. Examples 46-51 were basically the same as Example 1, except that the types of substrates, Grignard reagents or electrophilic reagents were different. See Table 4 for details.

[0202] Table 4 Product yields of Examples 46-51

[0203]

[0204] The structural formula and structural characterization data of the target product A obtained in Examples 46-48 are consistent with those in Example 1.

[0205] Example 49 The structural formula of the target product X:

[0206]

[0207] The target product X has a yield of 71%, 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 6.96 (s, 2H), 6.85 (d,J=9.0 Hz,1H), 6.78 (d, J=9.0 Hz, 1H), 3.82 (s, 3H), 3.56 (s, 3H), 2.93 (septet, J=7.0Hz, 1H), 2.42 (septet, J=7.0 Hz, 2H), 2.19 (m, 2H), 1.82-1.60 (m, 8H), 1.41-0.90 (m, 12H), 1.31 (d, J =7.0 Hz, 6H), 1.16 (d, J=7.0 Hz, 6H), 0.92 (d, J=7.0 Hz, 6H). 31 P NMR (162 MHz, Chloroform-d) δ -1.62. 13C NMR (101 MHz, Chloroform-d) δ 156.51, 156.53, 152.54, 152.48, 147.14, 146.26, 146.13,139.59, 139.08, 132.90, 132.82, 127.05, 126.61, 120.44, 120.37, 110.92,108.88, 55.34, 54.92, 54.85, 36.95, 36.70, 34.09, 33.32, 32.96, 31.28, 31.09,30.73, 28.22, 28.11, 27.90, 27.72, 26.76, 25.38, 24.27, 23.89.

[0208] Example 50 The structural formula of the target product Y is:

[0209]

[0210] The target product Y has a yield of 69%, 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 6.98 (s, 2 H), 6.88 (d, J=8.8Hz, 1 H), 6.84 (d, J=8.8 Hz, 1 H), 3.79 (s, 3 H), 3.56 (s, 3 H), 2.96 (septet, J=6.8 Hz, 1 H), 2.51 (septet, J=6.6 Hz, 2 H), 1.33 (d, J=6.8 Hz, 6 H), 1.23 (d, J=6.6 Hz, 6 H), 1.16 (s, 9 H), 1.13 (s, 9 H), 0.95 (d, J=6.4 Hz, 6 H). 31 P NMR (162 MHz, CDCl3) δ 34.56. 13C NMR (101 MHz, Chloroform-d) δ155.68, 155.66, 152.38, 152.27, 146.96, 146.46, 140.18, 139.80, 132.79,132.72, 127.37, 126.91, 119.85, 110.66, 110.65, 108.00, 54.17, 53.77, 33.91,33.88, 33.62, 31.81, 31.64, 31.02, 30.99, 25.47, 24.08, 23.36.

[0211] Example 51 The structural formula of the target product Z is:

[0212]

[0213] The target product Z has a yield of 75%, 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 2.47 (s, 3H), 2.24 (s, 3H), 2.20 (s, 6H), 2.14 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 210.17, 141.09135.45, 133.14, 127.02, 33.16, 17.13, 16.76, 16.01.

[0214] Comparative Example 1 Synthesis of Target Product H

[0215] Compared with Example 27, this example adopts an intermittent process to synthesize compound H, and compares it with the technical route of the present invention in terms of experimental operation, product yield and economic effect, which proves the creativity and beneficial effects of the present invention.

[0216] The comparative example synthesis route is as follows:

[0217] .

[0218] 1) Take a 500 mL three-necked flask equipped with a reflux tube and a stirrer, add 1.22 g of magnesium chips (50 mmol), protect with nitrogen, and then add 45 mL of tetrahydrofuran, 55 mL of tetrahydrofuran solution of 2-N,N-dimethylaminobenzene magnesium bromide (55 mmol), and 1,2-bromochlorobenzene (5.8 mL, 50 mmol) to the three-necked flask in sequence. Heat the reaction mixture to 60°C. After 2.5 hours, cool the mixture to room temperature.

[0219] 2) Add cuprous chloride (5.94 g, 60 mmol) and dicyclohexylphosphonium chloride (12.3 mL, 55 mmol) to the mixture obtained in step 1) above and stir at room temperature for 16 hours, then filter the mixture and rinse with hexane (2×50 mL). Transfer the solid to a 500 mL reaction bottle, add ether (150 mL) and ammonia (200 mL), and stir for 2 hours.

[0220] 3) The mixture obtained in step 2) was transferred to a separatory funnel and ammonia (500 mL) and ether (200 mL) were added. The layers were separated and the aqueous layer was further extracted with ether (2×200 mL). The organic layers were combined and washed with ammonia (2×150 mL) and saturated brine (150 mL), then dried over sodium sulfate and concentrated under vacuum. The residue was recrystallized from hot methanol to obtain the target product H with a yield of 46% as a white solid with a purity of 98% by HPLC.

[0221] Compared with Comparative Example 1, the present invention avoids the use of magnesium chips and cuprous chloride, effectively avoids metal residues and the cumbersome operation of removing metallic copper in post-treatment. In addition, the technical solution of the present invention greatly improves the yield of the target compound H, and has significant economy, greenness and efficiency.

[0222] Comparative Example 2 Synthesis of Target Product H

[0223] Compared with Example 27, this example adopts an intermittent process to synthesize compound H, and compares it with the technical route of the present invention in terms of experimental operation, product yield and economic effect, which proves the creativity and beneficial effects of the present invention.

[0224] The comparative example synthesis route is as follows:

[0225] .

[0226] 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 then protect it with nitrogen. Then, add magnesium chips (1.44 g, 60 mmol) and iodine (0.25 g, 1 mmol) under a nitrogen atmosphere to close the reaction system. Then, add 50 mL of tetrahydrofuran to the reaction bottle through a double-ended needle, and transfer the tetrahydrofuran solution of 2-N,N-dimethylaminobromobenzene (50 mmol) to the constant pressure dropping funnel. Stir the reaction device at room temperature, heat it to reflux with a hair dryer, and keep reflux for 10 minutes before adding the tetrahydrofuran solution of 2-N,N-dimethylaminobromobenzene dropwise. The reaction solution gradually turns grayish white, and then continue to add the remaining tetrahydrofuran solution of 2-N,N-dimethylaminobromobenzene dropwise under stirring at room temperature. After the addition is complete, continue stirring at room temperature for 1 hour, and then reflux for another 1 hour.

[0227] 2) After the above step 1) is completed, transfer the tetrahydrofuran solution of 2-chlorobromobenzene (20 mmol) to a constant pressure dropping funnel and add dropwise under reflux for 20 minutes. After the addition is complete, continue the reflux reaction for 12 hours. Cool the reaction system to room temperature, then add cuprous chloride (3.56 g, 24 mmol) and dicyclohexylphosphonium chloride (7.38 mL, 22 mmol) to the reaction mixture and stir at room temperature for 16 hours.

[0228] 3) After the reaction, filter the mixture and rinse with dichloromethane (2×50 mL). Transfer the mother liquor to a separatory funnel and add ammonia (200 mL) and ether (50 mL). Separate the layers and further extract the aqueous layer with ether (2×50 mL). Combine the organic layers and wash with ammonia (2×50 mL) and saturated brine (50 mL), then dry over sodium sulfate and concentrate under vacuum. Recrystallize the residue with hot methanol to obtain the target product H with a yield of 49% as a white solid with a purity of 97% by HPLC.

[0229] Compared with Comparative Example 2, the present invention avoids the use of excessive aryl Grignard reagent, reducing the original 2.5-3.0 equivalents to 1.2 equivalents. In addition, the introduction and removal of metal catalysts are also avoided, meeting the requirements of green chemistry.

[0230] It can be seen from the above embodiments that the continuous synthesis method of 1,2-disubstituted aromatic compounds of the present invention has a wide range of substrate adaptability, and the substrate, Grignard reagent and electrophilic reagent can be changed according to needs to obtain 1,2-disubstituted aromatic compounds, which has broad application prospects.

[0231] 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 1,2-disubstituted aromatic compounds, characterized in that: The following steps are involved: Step S1: using a tetrahydrofuran solution of substrate 1,2-dihalobenzene as feed liquid A, and using a tetrahydrofuran solution of isopropylmagnesium chloride·lithium chloride as feed liquid B; mixing feed liquid A and feed liquid B, and then performing a magnesium-halide exchange reaction to obtain a reaction liquid E; The concentration of the substrate 1,2-dihalobenzene in the feed solution A is 0.65-1.3 mol / L; the concentration of isopropylmagnesium chloride·lithium chloride in the feed solution B is 1.3 mol / L; the molar ratio of the substrate 1,2-dihalobenzene to isopropylmagnesium chloride·lithium chloride is 1:1-1.3; Step S2: subjecting the reaction solution E to an elimination reaction to obtain a reaction solution F containing a benzylene intermediate; Step S3: using a Grignard reagent solution as a feed solution C, mixing the feed solution C and the reaction solution F, and then performing an addition reaction to obtain a reaction solution G containing an ortho-substituted aryl Grignard reagent; The concentration of the Grignard reagent solution is 0.25-2.0 mol / L; the molar ratio of the substrate 1,2-dihalobenzene in step S1 to the Grignard reagent in step S3 is 1:1.1-1.3; Step S4: using a solution containing an electrophilic reagent as a feed solution D, mixing the feed solution D with a reaction solution G, and then performing a nucleophilic substitution reaction to obtain a reaction solution H containing a target product, a 1,2-disubstituted aromatic compound; The concentration of the electrophilic reagent solution is 0.5 or 1.0 mol / L; the molar ratio of the substrate 1,2-dihalogenated benzene in step S1 to the electrophilic reagent in step S4 is 1:1.2-2.0; Step S5: receiving and quenching the reaction solution H with a saturated aqueous ammonium chloride solution, and then obtaining the target product 1,2-disubstituted aromatic compound after separation, drying, concentration and purification.

2. The continuous synthesis method of a 1,2-disubstituted aromatic compound according to claim 1, characterized in that: The 1,2-dihalogenated benzene has a structure as shown in the following formula I; the intermediate product contained in the reaction solution E has a structure as shown in the following formula II; the intermediate product contained in the reaction solution F has a structure as shown in the following formula III; the intermediate contained in the reaction solution G has a structure as shown in the following formula IV; the target product 1,2-disubstituted aromatic compound has a structure as shown in the following formula V: ； Wherein X1 is iodine or bromine, X2 is bromine or chlorine; R1 and R2 are the same or different substituents, including hydrogen atoms or alkyl groups; X is bromine or chlorine; R3 is an aryl group, a cycloalkyl group or a chain alkyl group; R4 is a substituent produced by a nucleophilic substitution reaction of an aldehyde, a ketone, an amide, an ester, an isocyanate, an anhydride, a Weinreb amide, a halogen, a cyano group or a chlorophosphine group.

3. The continuous synthesis method of a 1,2-disubstituted aromatic compound according to claim 1, characterized in that: In step S3, the Grignard reagent is an aryl or alkyl Grignard reagent; and the Grignard reagent solution is a Grignard reagent solution in tetrahydrofuran or 2-methyl-tetrahydrofuran.

4. The continuous synthesis method of a 1,2-disubstituted aromatic compound according to claim 1, characterized in that: In step S4, the electrophilic reagent is a chemical reagent that reacts with a Grignard reagent, including aldehydes, ketones, amides, esters, isocyanates, anhydrides, Weinreb amides, halogens, cyano groups or chlorophosphine; and the electrophilic reagent-containing solution is a tetrahydrofuran or 2-methyltetrahydrofuran solution of the electrophilic reagent.

5. A device for realizing the continuous synthesis method of 1,2-disubstituted aromatic compounds according to claim 1, characterized in that: The device comprises a first feed pump, a second feed pump, a third feed pump, a fourth feed pump, a first mixer, a second mixer, a third mixer, a first microreactor, a second microreactor, a third microreactor, a fourth 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 third feed pump and the second mixer are connected by a pipeline, the fourth feed pump and the third mixer are connected by a pipeline, and the first mixer, the first microreactor, the second microreactor, the second mixer, the third microreactor, the third mixer, the fourth microreactor, the back pressure valve and the receiving device are sequentially connected by a pipeline; The device is used to continuously synthesize 1,2-disubstituted aromatic compounds, and 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 halide exchange reaction to obtain a reaction liquid E; the reaction liquid E continues to flow into a second microreactor to perform an elimination reaction to obtain a reaction liquid F containing a benzyne intermediate; feed liquid C is fed by a third feed pump, so that feed liquid C and reaction liquid F are simultaneously pumped into a third microreactor through a second mixer to perform an addition reaction to obtain a reaction liquid G containing an ortho-substituted aromatic Grignard reagent; The feed liquid D is fed by the fourth feed pump, and the feed liquid D and the reaction liquid G are mixed in the third mixer and then enter the fourth microreactor to perform a nucleophilic substitution reaction to obtain a reaction liquid H containing the target product 1,2-disubstituted aromatic compound; the reaction liquid H 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 1,2-disubstituted aromatic compound is obtained after liquid separation, drying, concentration and purification.

6. The device according to claim 5, characterized in that: The retention time of the reaction solution E in the first microreactor is 20-80 seconds; the reaction temperature of the reaction solution E in the first microreactor is -20-25°C.

7. The device according to claim 5, characterized in that: The retention time of the reaction solution F in the second microreactor is 2-5 minutes; the reaction temperature of the reaction solution F in the second microreactor is 70-100°C.

8. The device according to claim 5, characterized in that: The retention time of the reaction liquid G in the third microreactor is 20-60 seconds; the reaction temperature of the reaction liquid G in the third microreactor is 25-60°C; the retention time of the reaction liquid H in the fourth microreactor is 2-6 minutes; the reaction temperature of the reaction liquid H in the fourth microreactor is 25-60°C.

Images