A continuous flow process for the synthesis of (S)-DPPNH2 class of ortho-disubstituted N, P ligands

Abstract

The application discloses a continuous flow synthesis process of (S)-DPPNH2 type o-bisphenyl-substituted N, P ligand, which comprises the following steps: after a substrate o-dibromobenzene I solution and a lithium reagent A are mixed through a first mixer, the mixture is input into a first reactor to perform a first Br / Li exchange reaction; the reaction solution is input into a second reactor after being mixed with a diphenyl chlorophosphine II solution through a second mixer; the reaction solution is input into a third reactor after being mixed with a lithium reagent B through a third mixer to perform a second Br / Li exchange reaction; finally, the reaction solution is input into a fourth reactor after being mixed with a tert-butyl sulfinamide III solution through a fourth mixer; after being stable, the reaction solution is taken out, quenched and purified to obtain a key intermediate compound IV, and then the target compound V is obtained through deprotection. The process has wide substrate applicability, can quickly construct a (S)-DPPNH2 type ligand compound library, and provides an efficient and convenient platform technology for the large-scale and on-demand synthesis of o-bisphenyl-substituted N, P chiral ligands.

Description

Technical Field

[0001] This invention belongs to the field of continuous flow synthesis technology, specifically relating to a continuous flow synthesis process for (S)-DPPNH2 type o-phenyl disubstituted N, P ligands. Background Technology

[0002] Chiral N and P ligands are a class of highly active ligands widely used in organometallic catalysis. Significant progress has been made in their structural design and catalytic application research. Existing technologies mainly include: 1. Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry; 2. Mechanistic study on the side arm effect in a palladium / Xu-Phos-catalyzedenantioselective alkoxyalkenylation of γ-hydroxyalkenes. Among them, a series of N and P ligands derived from the chiral aminophosphine (S)-o-diphenylphosphine phenethylamine ((S)-DPPNH2) as the backbone have broad application prospects in asymmetric catalytic reactions. Representative ligands include PEAPhos-type ligands and phosphine imine-type ligands developed by Hu Xiangping et al., and Ming-Phos, Xu-Phos, and W-Phos developed by Zhang Junliang et al. These ligands have been widely used in various asymmetric catalytic systems, and their relevant structural formulas are shown below:

[0003] Using o-dibromobenzene as a substrate and organolithium reagents for Br / Li exchange reactions is a common method for synthesizing o-disubstituted benzene compounds. This method is relatively simple to operate and the reagents are inexpensive. However, the organolithium intermediates generated during the reaction (such as o-bromophenyllithium) are extremely reactive. Even at ultra-low temperatures below -100 °C, they readily undergo elimination reactions to generate highly reactive benzyne intermediates, which in turn trigger various side reactions, resulting in poor reaction selectivity and limiting the scope of applications.

[0004] Therefore, there is an urgent need in this field to develop an efficient, rapid, and simple synthetic process that can effectively suppress benzyne side reactions and avoid highly active intermediate volume types, so as to realize the large-scale and on-demand preparation of ortho-disubstituted benzene N, P chiral ligands, and further expand their application in transition metal catalytic asymmetric synthesis. Summary of the Invention

[0005] To address the shortcomings of existing technologies, such as the stringent conditions of the Br / Li exchange reaction, the susceptibility to benzyne elimination side reactions, poor selectivity, and difficulty in achieving large-scale production, this invention employs a multi-stage mixed series continuous flow reaction system to complete the synthesis operation. The structure of the supporting continuous flow equipment is as follows: Figure 1 As shown, this is only used to complete the continuous flow synthesis process defined in this invention. This process integrates ultra-low temperature rapid Br / Li exchange reaction, second-level precise residence time control, and multi-step synthesis operations into the same continuous flow reaction platform, which can effectively achieve milder reaction conditions, more efficient production operations, and expand the applicable substrate range, providing a simple and feasible synthesis scheme for the industrial preparation of (S)-DPPNH2-like ortho-disubstituted N, P ligands.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is: a continuous flow synthesis process for (S)-DPPNH2-type o-phenyl disubstituted N,P ligands, comprising the following steps: The substrate o-dibromobenzene I solution and lithium reagent A are mixed in the first mixer and then fed into the first reactor for the first Br / Li exchange reaction. The effluent after the reaction enters the second mixer, is mixed with diphenylphosphine chloride II solution, and then fed into the second reactor for the second reaction. The effluent after the reaction enters the third mixer, is mixed with lithium reagent B, and then fed into the third reactor for the second Br / Li exchange reaction. The effluent after the reaction enters the fourth mixer, is mixed with tert-butylsulfinamide III solution, and then fed into the fourth reactor for the fourth reaction. After the reaction is stabilized, the reaction solution is collected, quenched and purified to obtain intermediate compound IV, and then deprotected to obtain target compound V. The structural formulas of compounds I, II, III, IV, and V are shown below:

[0007] Wherein, the substituent R of compound III is selected from one of alkyl, aromatic, and aromatic heterocyclic groups.

[0008] Preferably, lithium reagent A and lithium reagent B are selected from at least one of n-butyllithium, sec-butyllithium, tert-butyllithium, n-hexyllithium, or phenyllithium.

[0009] Preferably, lithium reagent A is n-hexyllithium and lithium reagent B is n-butyllithium.

[0010] Preferably, based on the amount of compound I, the amount of compound II is 1.0 to 1.5 equivalents, and the amount of compound III is 1.0 to 1.5 equivalents.

[0011] Preferably, the amount of lithium reagent A is 1.0 to 1.2 equivalents, and the amount of lithium reagent B is 1.0 to 1.2 equivalents.

[0012] Preferably, the residence time in the first reactor is 0.5 to 4.0 seconds, the residence time in the second reactor is 2.2 to 7.2 seconds, the residence time in the third reactor is 0.9 to 2.2 seconds, and the residence time in the fourth reactor is 0.7 to 12.3 seconds.

[0013] Preferably, the synthesis process is carried out at -80°C to -40°C.

[0014] The beneficial effects of this invention are: (1) The present invention adopts a continuous flow synthesis process, which realizes the continuous implementation of the Br / Li exchange reaction, which is difficult to control and requires ultra-low temperature of -120 to -100 ℃ in traditional batch operation. The reaction temperature can be raised to about -70 ℃, which is easy to control in industrial production. The reaction residence time is greatly shortened to less than 30 seconds. The highest total yield of the target product can reach 71%, and the diastereoselectivity can reach up to 98:2 dr. The overall operation is simple, the process is stable, and it has a wide range of applicable substrates.

[0015] (2) This invention uses inexpensive and readily available o-dibromobenzene as a starting material. In a continuous flow system, an active but unstable organolithium intermediate is prepared in situ via selective lithium bromide exchange. This intermediate is then reacted with electrophilic reagents of different structures to efficiently and rapidly construct a series of (S)-DPPNH2-type o-phenyl disubstituted N,P chiral ligand compounds. Experiments have confirmed that this synthetic method exhibits excellent functional group tolerance to various functional groups, including alkyl, aryl, heteroaryl, halogen, nitro, and alkoxy groups.

[0016] (3) This invention constructs a highly versatile continuous flow synthesis platform technology. By simply changing the type of electrophilic reagent and adjusting the material ratio, residence time, and reaction temperature in combination with substrate and reactivity adaptation, various (S)-DPPNH2 chiral ligands with different structures can be directionally prepared. Compared with traditional metal-catalyzed synthesis routes, this invention has low raw material costs, short reaction flow, and high synthesis efficiency, making it economically practical. It can provide efficient and feasible technical support for the rapid screening and large-scale preparation of chiral ligands in the fields of asymmetric catalysis and medicinal chemistry research. Attached Figure Description

[0017] Figure 1 This is a schematic diagram of the overall structure of a continuous flow synthesis apparatus for synthesizing (S)-DPPNH2-type phthalic disubstituted N, P ligands.

[0018] In the diagram: 11-First mixer, 12-Second mixer, 13-Third mixer, 14-Fourth mixer; 21-First reactor, 22-Second reactor, 23-Third reactor, 24-Fourth reactor; 31-First feed pump, 32-Second feed pump, 33-Third feed pump, 34-Fourth feed pump, 35-Fifth feed pump.

[0019] The T °C shown in the attached figure is the pre-cooling process temperature of the reactant feed and pipeline system in the continuous flow synthesis apparatus. Detailed Implementation

[0020] The following specific embodiments illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0021] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials and reagents used in the following examples are commercially available. For examples where specific conditions are not specified, conventional conditions or conditions recommended by the manufacturer are followed. For reagents or instruments whose manufacturers are not specified, they are all commercially available products.

[0022] In the following embodiments, unless otherwise specified, the techniques or conditions are performed in accordance with conventional techniques or conditions in the art, or in accordance with the product instructions; the amount of compound used is in equivalent quantities.

[0023] 1. The synthesis method of compound III in the following examples is as follows: An aldehyde (1.0 equivalent) was dissolved in tetrahydrofuran (THF), and optically pure tert-butylsulfinamide (1.0 equivalent) and tetraisopropyl titanate (1.2 equivalent) were added. The mixture was stirred overnight at room temperature. After the reaction was complete, water and ethyl acetate were added and stirred. The mixture was filtered under reduced pressure, and the filter cake was washed with ethyl acetate. The filtrate was collected, dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure, and purified to obtain compound III.

[0024] 2. Construction of the continuous flow synthesis apparatus The continuous flow synthesis apparatus includes a first mixer 11, a first reactor 21, a second mixer 12, a second reactor 22, a third mixer 13, a third reactor 23, a fourth mixer 14, and a fourth reactor 24, connected sequentially by connecting pipes, as well as a first feed pump 31, a second feed pump 32, a third feed pump 33, a fourth feed pump 34, a fifth feed pump 35, and a precooling pipe. The first feed pump 31 and the second feed pump 32 are respectively connected to the first mixer 11 via the precooling pipe; the third feed pump 33, the fourth feed pump 34, and the fifth feed pump 35 are respectively connected to the second mixer 12, the third mixer 13, and the fourth mixer 14 via the precooling pipes.

[0025] In this embodiment, the first mixer 11, the second mixer 12, the third mixer 13, and the fourth mixer 14 are all static mixers; the first reactor 21, the second reactor 22, the third reactor 23, and the fourth reactor 24 are all coil reactors. The coil reactors, connecting pipes, and precooling pipes are made of 1 / 16-inch outer diameter polytetrafluoroethylene pipes or 316L stainless steel pipes; the first to fifth feed pumps are injection pumps and / or horizontal flow pumps.

[0026] Examples 1-14 below investigate the effects of reaction temperature, reagent dosage, and residence time on the reaction effect through the synthesis of compound IV-1.

[0027] Example 1

[0028] The continuous flow synthesis apparatus was immersed in a 70°C cooling bath. Using an HPLC pump, o-dibromobenzene (I, 1.0 equivalent) and n-hexyllithium (1.0 equivalent) were fed into the first reactor 21 via the first mixer 11, with a residence time of 1.3 s for Br / Li exchange. Then, the mixture was fed into the second mixer 12 and mixed with a tetrahydrofuran solution of diphenylphosphine chloride (II, 1.2 equivalent) before being fed into the second reactor 22, with a residence time of 4.9 s. Next, it was fed into the third mixer 13 and mixed with n-butyllithium (1.0 equivalent) before being fed into the third reactor 23, with a residence time of 1.83 s. Finally, it was fed into the fourth mixer 14 and mixed with a tetrahydrofuran solution of N-(tert-butylsulfinyl)ethylimine (III, 1.2 equivalent) before being fed into the fourth reactor 24, with a residence time of 9.74 s. After stable operation, the reaction solution was collected, quenched, and purified to obtain the main diastereomeric compound IV1 in pure form, with a yield of 69%, as a colorless solid. The obtained product was characterized, and the results are as follows: [α] 25 D = -77.3° (c 1.00, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ = 7.49 (dd, J = 7.9, 4.3 Hz, 1H), 7.39 - 7.30 (m, 7H), 7.30 - 7.23(m, 4H), 7.16 (td, J = 7.5, 1.3 Hz, 1H), 6.96 - 6.89 (m, 1H), 5.51 - 5.38 (m,1H), 3.48 (d, J = 4.1 Hz, 1H), 1.36 (d, J = 6.6 Hz, 3H), 1.12 (s, 9H). 13 C NMR(101 MHz, CDCl3) δ = 148.64, 148.41, 136.75, 136.65, 136.51, 136.41, 135.15(d, J = 14.5 Hz), 134.22, 134.00 (d, J = 3.8 Hz), 133.93, 133.78, 129.42,128.87, 128.72, 128.61 (d, J = 2.6 Hz), 128.54 (d, J = 2.4 Hz), 127.48,126.76 (d, J = 5.2 Hz), 52.31 (d, J = 27.6 Hz), 24.89, 22.53 (3C). 31 P NMR (243 MHz, CDCl3) δ = -17.66. HRMS (ESI) m / z calcd for C 24 H 28 NOPS [M+H] + :410.1629, found: 410.1632. Examples 2-3 and Comparative Examples 1-3 are basically the same as Example 1, except that lithium reagent A and lithium reagent B are selected. The effect of different lithium reagents A and B on the yield of compound IV-1 is shown in Table 1 below.

[0029] Table 1

[0030] Table 1 shows that when lithium reagent A is n-hexyllithium and lithium reagent B is n-butyllithium, the yield reaches 69%. N-hexyllithium is relatively mild, which is beneficial for improving the selectivity of the first Br / Li exchange reaction, but its reaction rate is slower in the second Br / Li exchange. Therefore, using the more reactive n-butyllithium in the second Br / Li exchange helps to improve the yield. Furthermore, Comparative Example 13 shows that the choice of lithium reagent in the first Br / Li exchange has a significant impact on the reaction results: when lithium reagent A is sec-butyllithium or phenyllithium, the product yield decreases significantly; when lithium reagent A is tert-butyllithium, multiple batches experienced equipment blockage, and the collected reaction solution had a complex composition with no major product.

[0031] Examples 4-14 and Comparative Examples 4-5 were operated in basically the same manner as Example 1, except for the reaction temperature, reagent dosage, and residence time. The effect of the above parameters on the yield of compound IV-1 is shown in Table 2 (where T1 represents the residence time in the first reactor R1).

[0032] Table 2

[0033] As shown in Table 2, the continuous flow selective Br / Li exchange process developed in this invention is simple, efficient, and rapid. It improves the harsh reaction conditions by raising the reaction temperature to a more moderate range of -80 to -40 °C and shortening the reaction time to 12.33 to 21.6 s, while achieving a product yield of over 52%. Furthermore, as shown in Comparative Examples 4 and 5, in the first Br / Li exchange reaction, a reaction time that is too short leads to incomplete reaction, while a reaction time that is too long causes over-reaction and increases the impurity content.

[0034] Comparative Example 6 This embodiment is basically the same as embodiment 1, except that the four static mixers are replaced with T-shaped tees.

[0035] Multiple batches were run under these conditions, and all resulted in equipment blockage, with complex compositions of the collected reaction solution and no major product. The ordinary T-type tee has poor mixing performance and is unsuitable for rapidly exothermic, highly selective reactions.

[0036] Example 15, Synthesis of Compound V Compound IV-1 (1.0 equivalent) obtained in Example 1 and methanol were added to a round-bottom flask. 2M hydrochloric acid solution was added until the pH was less than 3. The mixture was stirred at room temperature for 30 minutes. The methanol was removed by concentration under reduced pressure. Water was added, and the aqueous solution was washed with ethyl acetate. The pH was adjusted to 12 at 0°C with 2M sodium hydroxide solution. The aqueous phase was extracted with dichloromethane. The organic phases were combined and washed with saturated brine. After drying with anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to obtain the enantiomer-enriched compound V in 95% yield as a white solid. The product was characterized, and the results are as follows: [α]25D = -44.8° (c 1.00, CH2Cl2). 1 H NMR (400 MHz, CDCl3)δ = 7.65 - 7.61 (m, 1H), 7.38 (td, J = 7.6, 1.4 Hz, 1H), 7.35 - 7.32 (m, 6H),7.29 - 7.27 (m, 3H), 7.26 - 7.24 (m, 1H), 7.14 (td, J = 7.5, 1.3 Hz, 1H), 6.87 - 6.83 (m, 1H), 4.98 - 4.91 (m, 1H), 2.11 (s, 2H), 1.26 (d, J = 6.5 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ = 147.77, 147.38, 137.03, 136.62, 134.21,134.01, 133.98, 133.78, 133.48, 129.66, 128.88, 128.82, 128.71, 128.64,128.59, 127.21, 125.52, 125.47, 48.22 (d, J = 26.7 Hz), 24.42. 31 P NMR (243MHz, CDCl3) δ = -16.64. HRMS (ESI) m / z calcd for C 20 H 20 NP [M+H]+: 306.1333, found: 306.1330. Compounds IV-2 to IV-33 were prepared in Examples 16-34. Examples 16-34 are basically the same as Example 1, except that the types of compounds III are different, as shown in Table 3 below.

[0037] Table 3

[0038] Example 16: Synthesis of Compound IV-2 After quenching and purification, the main diastereomeric compound IV-2 was obtained in pure form with a yield of 68%, as a white solid. The product was characterized as follows: [α]25D = -88° (c 1.00, CH2Cl2). 1 H NMR (400 MHz, CDCl3)δ = 7.49 - 7.41 (m, 1H), 7.40 (dd, J = 7.2, 1.4 Hz, 1H), 7.39 - 7.26 (m,10H), 7.20 (td, J = 7.4, 1.5 Hz, 1H), 7.07 - 6.98 (m, 1H), 5.34 - 5.22 (m,1H), 3.60 (s, 1H), 1.98 - 1.72 (m, 2H), 1.13 (s, 9H), 0.77 (t, J = 7.4 Hz,3H). 13 C NMR (101 MHz, CDCl3) δ = 147.62, 147.45, 137.00, 136.92, 136.60,136.53, 134.41, 134.10, 133.97, 133.85, 133.72, 129.32, 128.74, 128.61,128.54, 128.49, 127.38, 127.10 55.66, 55.62, 31.62, 22.51 (3C), 10.74. 31 P NMR(243 MHz, CDCl3) δ = -18.18. HRMS (ESI) m / z calcd for C 25 H 30 NOPS [M+H] + :424.1786, found: 424.1782. Example 17: Synthesis of Compound IV-3 After quenching and purification, the main diastereomeric compound IV-2 was obtained in pure form (66% yield) as a white solid. The product was characterized as follows: [α]25D = -84.3° (c 1.00, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ = 7.48 (dd, J = 7.9, 4.3 Hz, 1H), 7.40 (dd, J = 7.4, 1.4 Hz, 1H), 7.37 - 7.33 (m, 7H), 7.32 - 7.26 (m, 4H), 7.20 (td, 0.82 (d, J = 6.2 Hz, 3H), 0.76 (d, J = 5.9 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ = 148.35, 148.19, 136.96, 136.88, 136.58,136.51, 134.07, 133.98, 133.92, 133.84, 129.36, 128.71, 128.67, 128.56,128.53, 128.52, 128.48, 127.33, 60.82, 55.62, 25.03 (2C), 22.70, 22.48 (3C),21.78. 31 P NMR (243 MHz, CDCl3) δ = -18.36. HRMS (ESI) m / z calcd for C 27 H 34 NOPS[M+H] + : 452.2099, found: 452.2102. Example 18: Synthesis of Compound IV-4 After quenching and purification, the main diastereomeric compound IV-4 was obtained in pure form with a yield of 71%, as a white solid. The product was characterized as follows: [α]25D = -168° (c 1.00, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ = 7.44 (dd, J = 8.0, 4.4 Hz, 1H), 7.39 - 7.34 (m, 6H), 7.32 - 7.28(m, 5H), 7.25 - 7.20 (m, 2H), 5.68 (dd, J = 11.0, 3.8 Hz, 1H), 3.66 (d, J =3.8 Hz, 1H), 1.12 (s, 9H), 1.03 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ = 146.50,146.25, 138.18 (d, J = 11.7 Hz), 137.53 (d, J = 14.1 Hz), 136.82 (d, J = 11.7Hz), 135.49 (d, J = 2.3 Hz), 133.79, 133.71, 133.59, 133.52, 128.95 (d, J =5.0 Hz), 128.56, 128.46 (2C), 128.39 (2C), 128.33, 127.27, 63.25 (d, J = 29.2Hz), 55.61, 36.47, 27.28 (d, J = 2.6 Hz, 3C), 22.55 (3C). 31 P NMR (243 MHz, CDCl3) δ = -18.90. HRMS (ESI) m / z calcd for C 27 H 34 NOPS [M+H] + : 452.2099, found:452.2103. Example 19, Synthesis of Compound IV-5 After quenching and purification, the main diastereomeric compound IV-5 was obtained in pure form (69% yield) as a white solid. The product was characterized as follows: [α]25D = -61.1° (c 1.00, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ = 7.64 (dd, J = 8.0, 4.2 Hz, 1H), 7.38 (q, J = 5.9, 4.2 Hz, 1H), 7.34 - 7.25 (m, 3H), 7.27 - 7.12 (m, 8H), 7.12 - 6.99 (m, 6H), 6.68 - 6.58 (m, 1H), 3.88 (d, J = 4.0 Hz, 1H), 1.20 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ =146.76 (d, J = 24.2 Hz), 142.05, 135.01, 133.98, 133.84, 133.78, 133.65,129.33, 128.58, 128.53, 128.47, 128.42, 128.38, 128.34, 128.27, 127.99,127.69, 127.35, 60.07 (d, J = 26.9 Hz), 56.04, 22.73 (3C). 31 P NMR (243 MHz, CDCl3) δ = -18.28. HRMS (ESI) m / z calcd for C 27 H 34 NOPS [M+H] + : 472.1786, found:472.1788. Example 20: Synthesis of Compound IV-6 After quenching and purification, the main diastereomeric compound IV-5 was obtained in pure form (52% yield) as a white solid. The product was characterized as follows: [α]25D = -89.1° (c 1.00, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ = 8.39 (d, J = 8.2 Hz, 1H), 7.86 (dd, J = 8.0, 4.5 Hz, 1H), 7.73 (d,J = 7.0 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.51 - 7.42 (m, 4H), 7.29 (td, J =3.5, 1.6 Hz, 3H), 7.24 (d, J = 1.3 Hz, 1H), 7.22 - 7.16 (m, 2H), 7.13 - 7.04(m, 2H), 6.98 (t, J = 7.6 Hz, 2H), 6.87 (td, J = 7.6, 1.6 Hz, 2H), 6.77 (td,J = 8.0, 1.4 Hz, 1H), 3.78 (d,J = 2.2 Hz, 1H), 1.21 (s, 9H). 13 C NMR (101MHz, CDCl3) δ = 145.82 (d, J = 23.0 Hz), 136.97, 136.36, 134.78, 134.07,133.92, 133.86, 133.64, 133.45 (d, J = 19.0 Hz), 130.59, 128.94, 128.89,128.67 (d, J = 5.0 Hz), 128.55 (d, J = 12.0 Hz), 128.47 (d, J = 9.0 Hz), 128.41 (d, J = 6.0 Hz), 128.36, 127.72, 127.64, 127.28, 126.80, 125.77,124.80, 123.60, 56.00, 55.46 (d, J = 30.0 Hz), 22.76 (3C). 31 P NMR (243 MHz, CDCl3) δ = -18.70. HRMS (ESI) m / z calcd for C 33 H 32 NOPS [M+H] + : 522.1942, found:522.1947. Example 21: Synthesis of Compound IV-7 After quenching and purification, the main diastereomeric compound IV-7 was obtained in pure form (58% yield) as a white solid. The product was characterized as follows: [α]25D = -80.1° (c 1.00, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ = 7.75 - 7.70 (m, 1H), 7.66 (dd, J = 7.2, 2.2 Hz, 1H), 7.58 (d, J =8.6 Hz, 1H), 7.54 - 7.50 (m, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.43 - 7.39 (m,1H), 7.38 - 7.32 (m, 3H), 7.29 - 7.25 (m, 3H), 7.24 - 7.18 (m, 2H), 7.07 -6.98 (m, 6H), 6.80 (dd, J = 8.6, 3.8 Hz, 1H), 4.00 (d, J = 3.8 Hz (1H), 1.23 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ = 146.52 (d, J = 24.3 Hz), 139.28, 136.99 (d, J = 11.0 Hz), 136.13 (d, J = 15.8 Hz), 135.55 (d, J = 9.4 Hz), 135.00 (d,J = 2.0 Hz), 133.89, 133.75 (d, J = 2.9 Hz, 2C), 133.61, 133.01, 132.56,129.34, 128.52, 128.47, 128.43, 128.37, 128.35, 128.33, 128.14 (2C), 128.09,127.74, 127.40, 127.37, 125.96, 125.86, 125.77, 60.20 (d, J = 28.1 Hz),56.11, 22.75 (3C). 31 P NMR (243 MHz, CDCl3) δ = -18.19. HRMS (ESI) m / z calcdfor C 33 H 32 NOPS [M+H] + : 522.1942, found: 522.1945. Example 22, Synthesis of Compound IV-8 After quenching and purification, the main diastereomeric compound IV-8 was obtained in pure form, with a yield of 64%, as a white solid. The product was characterized as follows: [α]25D = -79.3° (c 1.00, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ = 7.90 (dd, J = 7.9, 4.4 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.37 -7.32 (m, 3H), 7.29 (d, J = 5.9 Hz, 1H), 7.26 - 7.20 (m, 2H), 7.14 (t, J = 7.4Hz, 1H), 7.10 - 7.02 (m, 3H), 6.99 (d, J = 3.6 Hz, 2H), 6.88 (q, J = 8.0 Hz,4H), 6.78 (dd, J = 7.5, 2.4 Hz, 1H), 3.44 (s, 1H), 2.54 (s, 3H), 1.26 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ = 146.59 (d, J = 24.0 Hz), 139.10, 137.38,136.77, 136.01, 135.11, 133.72, 133.64, 133.52, 133.45, 130.84, 128.90,128.68, 128.50, 128.43, 128.40, 128.27, 127.95, 127.88, 127.72, 127.46,125.75, 56.51 (d, J = 29.0 Hz), 55.96, 22.78 (3C), 19.35 (d, J = 5.4 Hz). 31 PNMR (243 MHz, CDCl3) δ = -18.15. HRMS (ESI) m / z calcd for C 30 H 32 NOPS [M+H]+:486.1942, found: 486.1940. Example 23: Synthesis of Compound IV-9 After quenching and purification, the main diastereomeric compound IV-8 was obtained in pure form (69% yield) as a colorless oil. The product was characterized as follows: [α]25D = -66.5° (c 1.00, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ = 7.65 (dd, J = 8.0, 4.3 Hz, 1H), 7.38 (td, J = 7.5, 1.5 Hz, 1H), 7.34 - 7.27 (m, 3H), 7.27 - 7.13 (m, 5H), 7.11 - 6.96 (m, 5H), 6.89 - 6.81 (m, 2H), 3.85 (d, J = 3.5 Hz, 1H), 2.08 (s, 3H), 1.21 (s, 9H). 13 C NMR (101MHz, CDCl3) δ = 146.84 (d, J = 24.0 Hz), 141.94, 138.01, 137.24, 136.97,136.31, 134.94, 134.03, 133.84 (2C), 133.65, 129.30, 128.98, 128.54, 128.51,128.46, 128.44, 128.35, 128.29, 128.25, 128.18, 128.08, 127.61, 124.74, 59.79(d, J = 28.1 Hz), 56.01, 22.76 (3C), 21.32. 31 P NMR (243 MHz, CDCl3) δ = -18.36. HRMS (ESI) m / z calcd for C 30 H 32 NOPS [M+H] + : 486.1942, found: 486.1943. Example 24: Synthesis of Compound IV-10 After quenching and purification, the main diastereomeric compound IV-9 was obtained in pure form (67% yield) as a white solid. The product was characterized as follows: [α]25D = -72.8° (c 1.00, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ = 7.68 - 7.61 (m, 1H), 7.38 (td, J = 7.6, 1.5 Hz, 1H), 7.30 (d, J =3.6 Hz, 3H), 7.25 - 7.20 (m, 3H), 7.19 - 7.13 (m, 3H), 7.07 - 6.98 (m, 5H), 6.87 (d, J = 7.9 Hz, 2H), 6.60 (dd, J = 8.4, 3.6 Hz, 1H), 3.85 (d, J = 3.7Hz, 1H), 2.20 (s, 3H), 1.20 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ = 146.98 (d, J= 24.1 Hz), 139.13, 137.08, 136.98, 136.03, 135.90, 134.96, 134.02, 133.83(d, J = 2.0 Hz), 133.65, 129.28, 129.09, 128.86, 128.51 (d, J = 2.2 Hz), 128.44, 128.29, 128.25, 128.21, 128.19, 127.97, 127.58, 122.91, 59.96 (d, J =28 Hz), 56.00, 22.74, 20.99. 31 P NMR (243 MHz, CDCl3) δ = -18.18. HRMS (ESI)m / z calcd for C 30 H 32 NOPS [M+H] + : 486.1942, found: 486.1942. Example 25: Synthesis of Compound IV-11 After quenching and purification, the main diastereomeric compound IV-10 was obtained in pure form (65% yield) as a white solid. The product was characterized as follows: [α]25D = -42.1° (c 1.00, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ = 7.65 - 7.57 (m, 1H), 7.37 (td, J = 7.6, 1.4 Hz, 1H), 7.30 (dt, J =4.0, 1.5 Hz, 3H), 7.26 - 7.17 (m, 6H), 7.13 - 7.08 (m, 2H), 7.06 - 7.00 (m,1H), 6.63 (dd, J = 9.3, 3.5 Hz, 1H), 6.36 (d, J = 2.3 Hz, 2H), 6.14 (t, J =2.3 Hz, 1H), 3.92 (d, J = 3.5 Hz, 1H), 3.55 (s, 6H), 1.22 (s, 9H). 13 C NMR(101 MHz, CDCl3) δ = 160.64, 160.46, 146.60 (d, J = 24.5 Hz), 144.60, 137.32(d, J = 11.1 Hz), 135.96 (d, J = 9.8 Hz), 135.85 (d, J = 14.9 Hz), 135.10,133.83, 133.70 (2C), 133.57, 129.44, 128.50, 128.48, 128.43, 128.41, 128.27,128.22, 127.73, 106.38 (d, J = 2.2 Hz), 105.89, 99.44, 99.30, 56.03, 55.15(2C), 55.12, 22.72(3C). 31 P NMR (243 MHz, CDCl3) δ = -18.82. HRMS (ESI) m / zcalcd for C 31 H 34 NO3PS [M+H] + : 532.1997, found: 532.2000. Example 26: Synthesis of Compound IV-12 After quenching and purification, the main diastereomeric compound IV-11 was obtained in pure form (34% yield) as a colorless oil. The product was characterized as follows: [α]25D = -89.4° (c 1.00, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ = 7.68 (dd, J = 7.7, 4.1 Hz, 1H), 7.38 (td, J = 7.6, 1.4 Hz, 1H), 7.30 (dt, J = 4.1, 1.5 Hz, 3H), 7.25 - 7.12 (m, 7H), 7.06 - 6.97 (m, 5H), 6.56 (dd, J = 8.4, 3.3 Hz, 1H), 3.77 (s, 1H), 2.85 (s, 6H), 1.20 (s, 9H). 13 CNMR (101 MHz, CDCl3) δ = 147.39 (d, J = 24.2 Hz), 137.36 (d, J = 12.0 Hz), 136.11 (d, J = 10.0 Hz), 135.80 (d, J = 16.0 Hz), 134.87, 133.98, 133.84,133.79, 133.65, 129.16, 129.08, 128.48 (2C), 128.42, 128.27, 128.20, 128.13,128.03, 127.97, 127.38, 123.53, 68.02 (2C), 59.43 (d, J = 27.4 Hz), 55.91, 22.78 (3C). 31 P NMR (243 MHz, CDCl3) δ = -18.13. HRMS (ESI) m / z calcd forC 31 H 35 N2OPS [M+H] + : 515.2208, found: 515.2210. Example 27: Synthesis of Compound IV-13 After quenching and purification, the main diastereomeric compound IV-12 was obtained in pure form (54% yield) as a white solid. The product was characterized as follows: [α]25D = -74.3° (c 1.00, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ = 7.65 (dd, J = 7.9, 4.1 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.36 -7.29 (m, 4H), 7.23 (q, J = 7.8 Hz, 5H), 7.12 - 7.01 (m, 7H), 6.59 (dd, J =8.2, 4.3 Hz, 1H), 3.98 (d, J = 4.3 Hz, 1H), 1.25 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ = 146.43 (d, J = 24.3 Hz), 140.61, 136.71 (d, J = 10.0 Hz), 136.08 (d, J = 15.8 Hz), 135.63 (d, J = 9.0 Hz), 135.31, 134.13, 133.93, 133.74,133.33, 129.65, 129.55, 128.79, 128.69, 128.61, 128.56, 128.49, 128.27 (d, J= 5.6 Hz), 128.00, 60.14 (d, J = 26.2 Hz), 56.29, 22.85 (3C). 31 P NMR (243MHz, CDCl3) δ = -18.19. HRMS (ESI) m / z calcd for C 29 H 29 ClNOPS [M+H] + : 506.1396, found: 506.1394. Example 28: Synthesis of Compound IV-14 After quenching and purification, the main diastereomeric compound IV-13 was obtained in pure form (53% yield) as a white solid. The product was characterized as follows: [α]25D = -87.2° (c 1.00, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ = 7.77 - 7.69 (m, 1H), 7.43 (td, J = 7.6, 1.4 Hz, 1H), 7.30 - 7.26(m, 3H), 7.26 - 7.14 (m, 3H), 7.12 - 7.06 (m, 3H), 7.06 - 7.02 (m, 1H), 6.99 (td, J = 8.1, 1.4 Hz, 2H), 6.96 - 6.85 (m, 3H), 3.75 (d, J = 4.2 Hz, 1H), 1.19 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ = 144.90 (d, J = 24.3 Hz), 136.83 (d,J = 10.4 Hz), 136.73, 136.47 (d, J = 16.7 Hz), 135.19 (d, J = 2.0 Hz), 134.73, 134.68, 134.12, 134.07, 133.93, 133.59, 133.46, 131.64 (d, J = 2.1Hz), 129.63, 129.51, 129.24, 128.49, 128.47, 128.45, 128.15, 128.10, 127.96,127.49, 126.78, 57.51 (d, J = 29.0 Hz), 56.26, 22.66 (3C). 31 P NMR (243 MHz, CDCl3) δ = -18.36. HRMS (ESI) m / z calcd for C 29 H 28 Cl2NOPS [M+H] + : 540.1006, found: 540.1007. Example 29: Synthesis of Compound IV-15 After quenching and purification, the main diastereomeric compound IV-14 was obtained in pure form (55% yield) as a white solid. The product was characterized as follows: [α]25D = -80.8° (c 1.00, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ = 7.73 - 7.64 (m, 1H), 7.44 (td, J = 7.6, 1.4 Hz, 1H), 7.36 - 7.33(m, 3H), 7.30 - 7.26 (m, 2H), 7.25 - 7.18 (m, 4H), 7.15 (dd, J = 8.6, 5.5 Hz, 2H), 7.09 - 7.04 (m, 3H), 6.77 (t, J = 8.7 Hz, 2H), 6.62 (dd, J = 8.3, 4.1Hz, 1H), 3.93 (d, J = 4.2 Hz, 1H), 1.24 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ =163.14, 160.69, 146.67, 146.43, 137.76 (d, J = 3.2 Hz), 136.76 (d, J = 10.3Hz), 136.00, 135.84, 135.66, 135.57, 133.98, 133.80 (d, J = 3.3 Hz), 133.62,129.90 (d, J = 8.3 Hz), 129.39, 128.65, 128.56, 128.49, 128.38, 128.31,128.09 (d, J = 5.6 Hz), 127.80, 115.28, 115.07, 59.82 (d, J = 26.5 Hz), 56.10, 22.73 (3C). 31 P NMR (243 MHz, CDCl3) δ = -18.27. 19 F NMR (565 MHz, CDCl3) δ = -115.24. HRMS (ESI) m / z calcd for C 29 H 29 FNOPS [M+H] + : 490.1691,found: 490.1690. Example 30: Synthesis of Compound IV-16 After quenching and purification, the main diastereomeric compound IV-15 was obtained in pure form, with a yield of 42%, as a white solid. The product was characterized as follows: [α]25D = -65.2° (c 1.00, CH2Cl2).1 H NMR (400 MHz, CDCl3) δ = 7.65 (dd, J = 8.0, 4.2 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.34 -7.25 (m, 9H), 7.20 (q, J = 7.6 Hz, 4H), 7.13 - 7.01 (m, 3H), 6.65 (dd, J =8.2, 4.7 Hz, 1H), 4.08 (d, 1H), 1.26 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ =146.03, 145.79, 145.75, 136.39, 136.07, 135.91, 135.37, 135.29, 133.96,133.79, 133.76, 133.60, 129.57, 129.52, 128.74, 128.59, 128.52, 128.49,128.45, 128.38, 128.29, 128.23, 128.05, 125.27 (q, J = 3.7 Hz), 60.44 (d, J =25.5 Hz), 56.27, 22.72 (3C). 31 P NMR (243 MHz, CDCl3) δ = -18.19. 19 F NMR (565MHz, CDCl3) δ = -62.63. HRMS (ESI) m / z calcd for C 30 H 29 F3NOPS [M+H] + : 540.1660, found: 540.1661. Example 31: Synthesis of Compound IV-17 After quenching and purification, the main diastereomeric compound IV-16 was obtained as a pure product in 31% yield, as a yellow liquid. The product was characterized as follows: [α]25D = -59.3° (c 1.00, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ = 7.57 (t, J = 7.2 Hz, 2H), 7.42 (t, J = 7.3 Hz, 1H), 7.30 (d, J =6.5 Hz, 4H), 7.25 - 7.23 (m, 1H), 7.21 - 7.11 (m, 6H), 7.07 - 7.01 (m, 4H), 6.60 (dd, J = 8.4, 4.7 Hz, 1H), 4.07 (s, 1H), 1.24 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ = 148.99, 148.05, 147.09, 137.98, 136.78, 135.44, 133.95, 133.75,133.54, 131.73, 129.67, 128.83, 128.79, 128.60, 128.52 (d, J = 2.0 Hz), 128.44, 128.21, 126.09, 124.86, 56.36, 32.66 (d, J = 14.0 Hz), 22.72 (3C). 31 PNMR (243 MHz, CDCl3) δ = -18.40. HRMS (ESI) m / z calcd for C 29 H 29 N₂O₃PS [M+H] + :517.1637, found: 517.1638. Example 32, Synthesis of Compound IV-18 After quenching and purification, the main diastereomeric compound IV-17 was obtained in pure form (50% yield) as a white solid. The product was characterized as follows: [α]25D = -84.7° (c 1.00, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ = 7.67 - 7.52 (m, 1H), 7.39 (td, J = 7.6, 1.4 Hz, 1H), 7.33 - 7.29(m, 3H), 7.27 (s, 1H), 7.25 - 7.19 (m, 5H), 7.13 - 7.06 (m, 3H), 7.05 - 7.00(m, 1H), 6.88 (dt, J = 3.1, 1.2 Hz, 1H), 6.81 (dd, J = 5.1, 1.4 Hz, 1H), 6.59(dd, J = 8.6, 4.5 Hz, 1H), 3.98 (d, J = 4.5 Hz, 1H), 1.18 (s, 9H). 13 C NMR(101 MHz, CDCl3) δ = 146.77 (d, J = 24.1 Hz), 143.43, 136.77 (d, J = 10.8Hz), 135.95 (d, J = 9.5 Hz), 135.75 (d, J = 15.3 Hz), 134.77, 133.88, 133.81,133.74, 133.68, 129.39, 128.62, 128.59, 128.51, 128.46, 128.40, 128.35,128.07 (d, J = 5.8 Hz), 127.75, 127.12, 125.94, 123.33 (d, J = 2.5 Hz),56.01, 29.71, 22.65 (3C). 31 P NMR (243 MHz, CDCl3) δ = -18.23. HRMS (ESI) m / zcalcd for C 27 H 28 NOPS2 [M+H] + : 478.1350, found: 478.1350. Example 33: Synthesis of Compound IV-19 After quenching and purification, the main diastereomeric compound IV-18 was obtained in pure form (45% yield) as a yellow oil. The product was characterized as follows: [α]25D = -132.2° (c 1.00, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ = 8.51 - 8.46 (m, 1H), 7.47 - 7.40 (m, 1H), 7.35 - 7.27 (m, 10H), 7.26 - 7.25 (m, 1H), 7.18 (td, J = 7.5, 1.4 Hz, 1H), 7.08 - 7.00 (m, 2H), 6.85 (d, J = 7.9 Hz, 1H), 6.70 (dd, J = 9.3, 4.2 Hz, 1H), 5.85 (d, J = 4.3Hz, 1H), 1.16 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ = 159.72, 148.35, 147.54 (d,J = 25.0 Hz), 136.69 (d, J = 10.8 Hz), 136.44, 136.36, 135.84 (d, J = 15.1Hz), 134.34, 134.16 (2C), 134.03 (2C), 133.92 (2C), 133.79 (2C), 129.53,129.23 (d, J = 5.7 Hz), 128.70, 128.65, 128.56, 128.51 (2C), 128.46, 127.67,122.77 (d, J = 3.5 Hz), 122.06, 59.36 (d, J = 26.9 Hz), 55.77, 22.64 (3C). 31 PNMR (243 MHz, CDCl3) δ = -17.78. HRMS (ESI) m / z calcd for C 28 H 29 N2OPS [M+H] + :473.1738, found: 473.1737. Example 40: Synthesis of Compound IV-20 After quenching and purification, the main diastereomeric compound IV-19 was obtained in pure form (55% yield) as a white oil. The product was characterized as follows: [α]25D = -101.2° (c 1.00, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ = 7.68 - 7.63 (m, 1H), 7.39 (td, J = 7.6, 1.5 Hz, 1H), 7.34 - 7.30(m, 3H), 7.30 - 7.27 (m, 2H), 7.25 - 7.20 (m, 4H), 7.18 - 7.13 (m, 2H), 7.01- 6.96 (m, 1H), 6.51 (dd, J = 9.3, 4.0 Hz, 1H), 5.71 (d, J = 3.1 Hz, 1H), 5.65 (dd, J = 3.1, 1.1 Hz, 1H), 3.95 (d, J = 4.0 Hz, 1H), 2.10 (s, 3H), 1.16 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ = 152.08, 151.88, 144.55 (d, J = 23.8 Hz), 136.75 (d, J = 10.6 Hz), 136.14 (d, J = 4.4 Hz), 136.06, 134.27, 133.95,133.92, 133.82, 133.79, 129.21, 128.65, 128.62, 128.61, 128.51, 128.46,128.26, 128.21, 127.93, 109.60, 106.17, 56.03, 54.57 (d, J = 29.6 Hz), 22.56 (3C), 13.50. 31 P NMR (243 MHz, CDCl3) δ = -17.81. HRMS (ESI) m / z calcd forC 28 H 30 NO2PS [M+H] + : 476.1735, found: 476.1738. As can be seen from the above embodiments, the continuous flow selective Br / Li exchange process of the present invention has a wide substrate adaptability range. The substituents of the electrophilic reagent can be changed according to the requirements to rapidly prepare a library of key intermediate compounds of (S)-DPPNH2 class compounds. Further transformation can be achieved through operations such as deprotection to prepare a variety of (S)-DPPNH2 class compounds.

[0039] This invention successfully streamlines the Br / Li exchange reaction, which is difficult to control in traditional batch operations and requires ultra-low temperatures of -120 to -100 °C. The reaction temperature is increased to -80 to -40 °C, and the reaction time is shortened to less than 30 seconds, achieving a maximum overall yield of 71% and a maximum diastereoselectivity of 98:2dr. This process has broad substrate applicability and can rapidly construct (S)-DPPNH2 ligand libraries, providing an efficient and convenient platform technology for the large-scale, on-demand synthesis of ortho-disubstituted benzene N,P chiral ligands.

[0040] Furthermore, by changing the type of imine and adjusting the reagent dosage, residence time, and reaction temperature according to the reactivity of the compound, different types of (S)-DPPNH2 compounds can be prepared as needed. This invention provides an economical and rapid method for the efficient synthesis of such compounds, and has broad application prospects.

[0041] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-disclosed technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A continuous flow synthesis process for (S)-DPPNH2-type phthalic disubstituted N,P ligands, characterized in that, The substrate o-dibromobenzene I solution and lithium reagent A are mixed in the first mixer and then fed into the first reactor for the first Br / Li exchange reaction. The effluent after the reaction enters the second mixer, is mixed with diphenylphosphine chloride II solution, and then fed into the second reactor for the second reaction. The effluent after the reaction enters the third mixer, is mixed with lithium reagent B, and then fed into the third reactor for the second Br / Li exchange reaction. The effluent after the reaction enters the fourth mixer, is mixed with tert-butylsulfinamide III solution, and then fed into the fourth reactor for the fourth reaction. After the reaction mixture stabilizes, it is collected, quenched and purified to obtain intermediate compound IV, and then deprotected to obtain target compound V; The structural formulas of compounds I, II, III, IV, and V are shown below: Wherein, the substituent R of compound III is selected from one of alkyl, aromatic, and aromatic heterocyclic groups.

2. The continuous flow synthesis process for (S)-DPPNH2-type o-phenyl disubstituted N,P ligands according to claim 1, characterized in that, The lithium reagent A and lithium reagent B are each selected from at least one of n-butyllithium, sec-butyllithium, tert-butyllithium, n-hexyllithium, or phenyllithium.

3. The continuous flow synthesis process for (S)-DPPNH2-type o-phenyl disubstituted N,P ligands according to claim 2, characterized in that, The lithium reagent A is n-hexyllithium, and the lithium reagent B is n-butyllithium.

4. The continuous flow synthesis process for (S)-DPPNH2-type o-phenyl disubstituted N,P ligands according to claim 1, characterized in that, Based on the amount of compound I, the amount of compound II is 1.0 to 1.5 equivalents, and the amount of compound III is 1.0 to 1.5 equivalents.

5. The continuous flow synthesis process for (S)-DPPNH2-type o-phenyl disubstituted N,P ligands according to claim 4, characterized in that, The amount of lithium reagent A used is 1.0 to 1.2 equivalents, and the amount of lithium reagent B used is 1.0 to 1.2 equivalents.

6. The continuous flow synthesis process for (S)-DPPNH2-type o-phenyl disubstituted N,P ligands according to claim 1, characterized in that, The residence time in the first reactor is 0.5 to 4.0 seconds, the residence time in the second reactor is 2.2 to 7.2 seconds, the residence time in the third reactor is 0.9 to 2.2 seconds, and the residence time in the fourth reactor is 0.7 to 12.3 seconds.

7. The continuous flow synthesis process for (S)-DPPNH2-type o-phenyl disubstituted N,P ligands according to claim 1, characterized in that, The synthesis process was carried out at -80 to -40 °C.

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