A method for high-throughput synthesis of 1-phenylazacyclobutane compounds

Abstract

This invention discloses a high-throughput synthesis method for 1-phenylazine heterocyclic butane compounds, comprising the following steps: in a solvent, the compound shown in Formula I and the compound shown in Formula II undergo a C-N coupling reaction in the presence of a catalyst and a base to obtain the 1-phenylazine heterocyclic butane compound shown in Formula III; wherein, R1 and R2 are any one of alkyl, halogen, aryl, substituted aryl, alkoxy, hydroxy, and nitrile groups; R3 is any one of F, Cl, Br, and I; and R4 is any one of hydroxyl, alkyloxy, H, halogen, and alkyl groups. This invention constructs a series of nitrogen heterocyclic compounds through high-throughput synthesis, obtaining a series of nitrogen heterocyclic compounds, and, through appropriate high-throughput screening, obtains the optimal reaction conditions in a very short time, thus solving the problems of the complexity of constructing carbon-nitrogen heterocycles and the difficulty in selecting conditions, as well as the high labor and time costs associated with existing synthetic methods.

Description

Technical Field

[0001] This invention relates to the field of nitrogen heterocyclic compounds, and more specifically, to a method for high-throughput synthesis of 1-phenyl-nitro-heterocyclic butane compounds. Background Technology

[0002] N-aryl heterocycles are of great importance to life because their structural subunits are present in many natural products. They are one of the most common structures found in bioactive compounds and are widely used throughout the chemical industry as basic intermediates or additives in the preparation of pharmaceuticals, herbicides, dyes, and many other compounds.

[0003] Chinese patent document CN101747249A discloses 1-diphenylmethyl-3-aminoazacyclobutane (D) or 1-diphenylmethyl-3-hydroxy-3-aminomethylazacyclobutane (I). The two azacyclobutanes obtained can be used as synthetic intermediates in the synthesis of antitumor, anti-inflammatory and other drugs. However, the reaction steps of this synthesis are relatively complex, and there is considerable room for improvement in reaction efficiency. Summary of the Invention

[0004] To address the problems of the existing technologies, and to solve the issues of the complexity of constructing carbon-nitrogen heterocycles, the difficulty in selecting conditions, and the high manpower and time costs associated with existing synthetic methods, this invention constructs a series of nitrogen heterocyclic compounds through high-throughput synthesis, and obtains a series of nitrogen heterocyclic compounds. Furthermore, through appropriate high-throughput screening, the optimal reaction conditions are obtained in a very short time.

[0005] To achieve one of the above objectives, this invention provides a method for high-throughput synthesis of 1-phenylazacyclobutane compounds. The technical solution adopted in this invention is as follows:

[0006] A method for high-throughput synthesis of 1-phenylazine compounds includes the following steps:

[0007]

[0008] In a solvent, the compound shown in Formula I and the compound shown in Formula II undergo a CN coupling reaction in the presence of a catalyst and a base to give the 1-phenylazacyclobutane compound shown in Formula III.

[0009] In the formula, R1 and R2 are any one of alkyl, halogen, aryl, substituted aryl, alkoxy, hydroxy, and nitrile groups; R3 is any one of F, Cl, Br, and I; and R4 is any one of hydroxyl, alkyloxy, H, halogen, and alkyl groups.

[0010] Preferably, the method includes: (a) supplying each of a plurality of reaction chambers with a compound of formula I or II, a base, a solvent, a transition metal, and a catalyst; (b) maintaining the plurality of reaction chambers under conditions suitable for forming a compound of formula III; (c) simultaneously purifying the plurality of compounds of formula III; and (d) evaluating one or more physicochemical properties of the purified compound III.

[0011] Preferably, the catalyst is selected from RuPhos, XPhos, BINAP, XantPhos, APhos, DPEphos, Brettphos, PPh3, PCy3, DPPP, CyJhonphos, DavePhos; and / or;

[0012] Preferably, the alkali is selected from DIPEA, Et3N, DBU, DBN, potassium tert-butoxide, sodium tert-butoxide, potassium phosphate, cesium carbonate, potassium carbonate, cesium fluoride, potassium acetate, and potassium methoxide.

[0013] Preferably, the solvent is selected from Dixane, DMSO, DMF, NMP, DMAc, THF, CAN, Tol, tBuOH, t-AmOH, nBuOH, and DME.

[0014] Preferably, the transition metal is selected from palladium acetate, Pd2(bda)3, allyl palladium chloride dimer, and Brettphos-Pd-G3.

[0015] Preferably, the multiple reaction chambers are multiple independent reaction flasks (each reaction flask is an independent reaction chamber) set in metal holes in a parallel reactor. The bottom of the parallel reactor has a first rubber pad for supporting the reaction flasks, and the top is provided with a metal cover. A second rubber pad is provided between the metal cover and the reaction flask, and a buffer film is provided between the second rubber pad and the reaction flask.

[0016] Furthermore, the method also includes simultaneously heating and stirring multiple reaction flasks using a heating stirrer after the reactants are added to the reaction flasks; and simultaneously rotary evaporating the multiple reaction flasks using a centrifugal rotary evaporator after the reaction is completed.

[0017] Furthermore, an inorganic base is first added to the reaction flask, followed by a magnetic stir bar, substrate, and catalyst, and finally a transition metal; and each material is added simultaneously to all reaction flasks at once through an auxiliary storage tank.

[0018] Furthermore, the heating stirrer supports the reaction flask via a metal tray; and the reaction speed is controlled at 600-700 rpm by a magnetic stir bar.

[0019] Furthermore, the catalyst used is BrettPhos, the solvent is DMF, the transition metal is Pd2(dba)3, and the base is Cs2CO3.

[0020] Furthermore, the ratio of the compound shown in Formula I to the compound shown in Formula II, the transition metal, the catalyst, and the base is 1:(1~2):(0.005~0.01):(0.02~0.04):(3~5).

[0021] Preferably, the reaction temperature of the CN coupling reaction is 90-110 °C and the reaction time is 12-24 h.

[0022] While screening reaction conditions and synthesizing related compounds can be achieved through conventional chemical methods, these methods are time-consuming, costly, and typically only provide specific solutions, not solutions for multiple compounds simultaneously. Current synthetic methods involve a slow process of changing and attempting to optimize each reaction parameter sequentially. This may include the type and concentration of the substrate, the base and transition metal and the type and stoichiometry of the transition metal, the type of solvent, and purification steps. Such gradual changes in reaction parameters lead to lengthy, comprehensive experiments and errors, making condition optimization even more laborious. Compared to conventional techniques, the present invention offers the following advantages:

[0023] 1) This invention provides a variety of complex high-throughput screening schemes for compounds, based on appropriate solvents, transition metals, types and equivalents of bases and substrates, to screen reactants and fully utilize the optimal catalytic reaction performance in the reaction system, thereby synthesizing the target compounds.

[0024] 2) This invention utilizes a high-throughput system based on a parallel reactor, a heating stirrer, and a centrifugal rotary evaporator to enable rapid feeding and modification of reaction conditions, providing a solution for high-throughput screening and synthesis of compounds. This system allows for the rapid screening of reaction conditions and the synthesis of target compounds. The high-throughput system's properties allow for the arduous process of changing multiple parameters, and experimental verification has shown that the high-throughput screening reaction of this invention features high yields and a simple and convenient reaction process. Attached Figure Description

[0025] The present invention will be further described below with reference to the accompanying drawings and embodiments.

[0026] Figure 1 The diagram illustrates the first round of screening for the synthesis of compound III, including the types of solvents, bases, catalysts, and transition metals.

[0027] Figure 2 The diagram illustrates the second round of screening for the synthesis of compound III, including the equivalents of compounds I and II, as well as the equivalents of base, catalyst, and transition metal.

[0028] Figure 3 The high-throughput synthesis system of compound III is illustrated. Detailed Implementation

[0029] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0030] All solvents used in this invention are of analytical grade. All substances used as raw materials in the examples were obtained through commercial purchase.

[0031] According to a preferred embodiment of the present invention, a method for high-throughput synthesis of 1-phenylazine compounds includes the following steps:

[0032]

[0033] In a solvent, the compound shown in Formula I and the compound shown in Formula II undergo a CN coupling reaction in the presence of a catalyst and a base to give the 1-phenylazacyclobutane compound shown in Formula III.

[0034] In the formula, R1 and R2 are any one of alkyl, halogen, aryl, substituted aryl, alkoxy, hydroxy, and nitrile groups; R3 is any one of F, Cl, Br, and I; and R4 is any one of hydroxyl, alkyloxy, H, halogen, and alkyl groups.

[0035] Specifically, the method includes: (a) supplying each of a plurality of reaction chambers with a compound of formula I or II, a base, a solvent, a transition metal, and a catalyst; (b) maintaining the plurality of reaction chambers under conditions suitable for the formation of a compound of formula III; (c) simultaneously purifying the plurality of compounds of formula III; and (d) evaluating one or more physicochemical properties of the purified compound III.

[0036] This invention is based on the following reaction principle: Under the action of a transition metal, the process proceeds through several steps. First, the active metal undergoes oxidative addition with a haloalkane, then undergoes transmetalation with an amine, and finally, reductive elimination yields the target product, while simultaneously producing a salt and an active metal to complete the catalytic cycle. Since coupling reactions have high requirements for the specific structure of the catalyst, a particular catalyst often exhibits good catalytic performance only for a specific type of reaction. High-throughput screening can rapidly compare the synthesis conditions of various substrates under different combinations of transition metals, bases, and solvents. To fully utilize the synergistic effect of the above mechanism, further high-throughput screening is preferably performed based on the following reactants to obtain the optimal reaction conditions:

[0037] The catalyst is selected from RuPhos, XPhos, BINAP, XantPhos, APhos, DPEphos, Brettphos, PPh3, PCy3, DPPP, CyJhonphos, and DavePhos.

[0038] The alkali is selected from DIPEA, Et3N, DBU, DBN, potassium tert-butoxide, sodium tert-butoxide, potassium phosphate, cesium carbonate, potassium carbonate, cesium fluoride, potassium acetate, and potassium methoxide.

[0039] The solvents are selected from Dixane, DMSO, DMF, NMP, DMAc, THF, CAN, Tol, tBuOH, t-AmOH, nBuOH, and DME.

[0040] The transition metal is selected from palladium acetate, Pd2(bda)3, allyl palladium chloride dimer, and Brettphos-Pd-G3.

[0041] To obtain high-throughput reaction conditions quickly and accurately, this invention utilizes a high-throughput system for the aforementioned high-throughput reaction. The high-throughput system includes a parallel reactor, a centrifugal rotary evaporator, and a heating stirrer.

[0042] The multiple reaction chambers consist of independent reaction flasks completely housed within metal orifices in a parallel reactor. The parallel reactor has a first rubber pad at the bottom to support the reaction flasks, a metal cap at the top, a second rubber pad between the metal cap and the reaction flasks, and a buffer film between the second rubber pad and the reaction flasks. Thus, the second rubber pad on the top reaction flask ensures a tight seal, and because the reaction flasks are completely enclosed by the metal orifices, and the first rubber pad at the bottom and the bottom itself are also encased in metal, the heat transfer in each reaction chamber of the parallel reactor is excellent.

[0043] The multiple reaction chambers are located on a single or multiple plates. In some embodiments, multiple plates or optionally a single plate may include at least 24 reaction chambers, such as at least 96 reaction chambers.

[0044] Furthermore, the heating stirrer supports the reaction flask via a metal tray, which better ensures the heat transfer efficiency between the heater and the reactor, guaranteeing a stable reaction temperature. The reaction liquid is encased in heated metal, preventing temperature differences between the upper and lower parts of the reaction liquid.

[0045] After the reactants are added to the reaction flasks, multiple reaction flasks are simultaneously heated and stirred using a heated stirrer; and after the reaction is complete, the multiple reaction flasks are simultaneously evaporated using a centrifugal rotary evaporator. In carrying out any of the methods of the present invention, purification may include liquid-phase preparation. In some embodiments, each reaction chamber is reacted with less than 1 mL of solvent.

[0046] When performing high-throughput screening reactions using this high-throughput system, an inorganic base is added to the reaction flask first, followed by a magnetic stir bar, substrate, and catalyst, and finally a transition metal. This prevents the magnetic stir bar from sticking to the bottom of the reaction flask during rotary evaporation of the solvent. Furthermore, each material is added simultaneously to all reaction flasks via an auxiliary storage tank, ensuring timely and consistent feeding.

[0047] When performing high-throughput screening, the reaction speed should be controlled at 600-700 rpm. 660 rpm is preferred. Too low a speed may result in insufficient mixing in the edge reactors, while too high a speed will cause excessively vigorous mixing, leading to the reaction liquid splashing onto the plastic film and increasing cross-contamination between materials.

[0048] Based on the above embodiments, the present invention selected the following substrates for the following specific experiments:

[0049] Compound I is selected from any one of the following compounds:

[0050]

[0051] Compound II is selected from any one of the following compounds:

[0052]

[0053] Product compound III is selected from any one of the following compounds:

[0054]

[0055] Example 1

[0056] From the perspective of the compatibility of CN-coupled reaction, this invention selects some raw materials with good compatibility for the reaction.

[0057] The 96-well plate (a parallel reactor has 96 independent metal wells, each containing 96 reaction flasks; A1, A2…A12…B1, B2…B12…H1, H2…H12 in this text are the well numbers of each well on the 96-well plate; the ellipsis indicates the sequential numbering based on a combination of letter row numbers and number column numbers) was transferred to a glove box. The inorganic base was added to the reaction flasks first, followed by the magnetic stir bar, substrate, and catalyst, and finally the transition metal. Each material was added simultaneously to all reaction flasks at once via an auxiliary storage tank. The specific materials are:

[0058] Catalysts: Add 0.01 mmol RuPhos to A1-H1, 0.01 mmol XPos to A2-H2, 0.005 mmol BINAP to A3-H3, 0.01 mmol XantPhos to A4-H4, 0.01 mmol APhos to A5-H5, 0.005 mmol DPEPhos to A6-H6, 0.01 mmol BrettPhos to A7-H7, 0.01 mmol PPh3 to A8-H8, 0.01 mmol PCy3 to A9-H9, 0.005 mmol DPPP to A10-H10, 0.01 mmol CyJhonPhos to A11-H11, and 0.01 mmol DavePhos to A12-H12.

[0059] Transition metals: Add 0.005 mmol Pd(OAc)2 to A1-A12, B1-B12, E1-E12, and F1-F12 respectively; add 0.0025 mmol Pd2(dba)3 to C1-C12, D1-D12, G1-G12, and H1-H12 respectively.

[0060] Substrate: Add 0.1 mmol I-1 to each of A1-A12, B1-B12, C1-C12, D1-D12, E1-E12, F1-F12, G1-G12, and H1-H12; add 0.15 mmol II-1 to each of A1-A12, B1-B12, C1-C12, D1-D12, E1-E12, F1-F12, G1-G12, and H1-H12.

[0061] Alkali: Add 0.4 mmol Cs2CO3 to A1-A12 and C1-C12 respectively; add 0.4 mmol K3PO4 to B1-B12 and D1-D12 respectively; add 0.4 mmol Cs2CO3 to E1-E12 and G1-G12 respectively; add 0.4 mmol K3PO4 to F1-F12 and H1-H12 respectively.

[0062] Solvent: Add 400 uL DMF to A1-A12, B1-B12, C1-C12, and D1-D12 respectively, and add 400 uL DMSO to E1-E12, F1-F12, G1-G12, and H1-H12 respectively.

[0063] After feeding is completed, seal the reactor, transfer the reactor out of the glove box, and place the reaction at 100 °C for 24 hours.

[0064] After screening in Example 1, a better catalyst, BrettPhos, and a better solvent, DMF, were obtained. The transition metal in the reaction of Example 1 was identified as Pd2(dba)3, and the base was Cs2CO3.

[0065] Example 2

[0066] Based on the results of Example 1, further high-throughput screening was conducted (A1, A2…A5…B1, B2…B5…E1, E2…E5 in the text are the numbers of each well in the multi-well plate; the ellipsis indicates the numbering arranged sequentially by a combination of letter row numbers and number column numbers). Since at least 2.0 eq of base is required in the metal coupling reaction, and reactant II is a hydrochloride salt, more base needs to be added to allow the reaction to proceed; therefore, the base equivalence was not carefully screened.

[0067] Transfer the reactor to the glove box;

[0068] Add 0.12 mmol of Ⅱ-1 to A1-A5 and B1-B5 respectively, add 0.2 mmol of Ⅱ-1 to C1-C5 and D1-D5 respectively, and add 0.15 mmol of Ⅱ-1 to E1-E5 respectively;

[0069] Add 0.1 mmol of I-1 to A1-A5, B1-B5, C1-C5, D1-D5, and E1-E5 respectively;

[0070] Add 0.001 mmol Pd2(dba)3 to A1-A5 and C1-C5 respectively, and add 0.0005 mmol Pd2(dba)3 to B1-B5 and D1-D5 respectively;

[0071] Add 0.004 mmol BrettPhos to A1-A5 and C1-C5 respectively, and add 0.002 mmol BrettPhos to B1-B5 and D1-D5 respectively;

[0072] Add 0.3 mmol Cs2CO3 to A1-D1 respectively, add 0.5 mmol Cs2CO3 to A2-H2 respectively, add 0.4 mmol sodium tert-butoxide to A3-D3 respectively, add 0.4 mmol CsF to A4-D4 respectively, and add 0.4 mmol K2CO3 to A5-D5 respectively;

[0073] Add 400 uL of DMF to A1-A5, B1-B5, C1-C5, D1-D5, and E1-E5 respectively;

[0074] After feeding is completed, seal the reactor, transfer the reactor out of the glove box, and place the reaction at 100 °C for 24 hours.

[0075] After screening in Example 2, a better compounding ratio was obtained, with the ratio of compound I to compound II, transition metal, catalyst, and base being 1:(1~2):(0.005~0.01):(0.02~0.04):(3~5).

[0076] Additionally, it should be noted that since high-throughput system sampling requires opening the reactor, but the reaction system is easily affected by air, leading to catalyst deactivation, a more stable reaction time was chosen for high-throughput screening based on research into the CN coupling reaction mechanism. Furthermore, because the reaction temperature of the high-throughput system must be uniform, the screening of reaction temperature was not included in the high-throughput screening.

[0077] Example 3

[0078] Based on the results of Examples 1 and 2, the optimal combination of transition metal, transition metal, catalyst and solvent was selected for the preparation of related compounds. Example 3 mainly shows the preparation of some compounds (the specific reaction steps of each compound will be listed in detail below).

[0079] Transfer the reactor to the glove box;

[0080] Add 0.1 mmol of I-1 to A1-D1, and then...

[0081] Add 0.1 mmol of I-2 to A2-D2, 0.1 mmol of I-3 to A3-D3, 0.1 mmol of I-4 to A4-D4, and 0.1 mmol of I-5 to A5-D5;

[0082] Add 0.2 mmol of II-1 to A1-A5 respectively, add 0.2 mmol of II-2 to B1-B5 respectively, add 0.2 mmol of II-3 to C1-C5 respectively, and add 0.2 mmol of II-4 to D1-D5 respectively;

[0083] Add 0.001 mmol Pd2(dba)3 to each of A1-A5, B1-B5, C1-C5, and D1-D5; add 0.004 mmol Brettphos to each of A1-A5, B1-B5, C1-C5, and D1-D5; add 0.5 mmol Cs2CO3 to each of A1-A5, B1-B5, C1-C5, and D1-D5; and add 400 μL DMF to each of A1-A5, B1-B5, C1-C5, and D1-D5.

[0084] After feeding is completed, seal the reactor, transfer the reactor out of the glove box, and place the reaction at 100 °C for 24 hours.

[0085] After the reaction was complete, some compounds were obtained through high-throughput preparation. Specific reaction information is as follows:

[0086] Reaction 1:

[0087]

[0088] 0.1 mmol of 1-bromo-3,5-difluorobenzene (Ⅰ-1) and 0.2 mmol of aziridine-3-ol hydrochloride (Ⅱ-1) were dissolved in a reactor containing 400 μL of DMF, with 0.001 mmol of Pd₂(dba)₃ as the transition metal, 0.004 mmol of Brettphos as the catalyst, and 0.5 mmol of Cs₂CO₃ as the base, at 100 °C. o The mixture was stirred at C for 24 h, and the reaction was monitored by TLC. Separation by column chromatography yielded a yellow solid with a yield of 88% and m / Z 186 [M+H]. + .

[0089] NMR characterization of compound 1 (yellow solid):

[0090] 1H NMR (400 MHz, CDCl3) δ 6.16 (tt, J = 9.3, 2.2 Hz, 1H), 5.90 (dd, J= 9.6, 2.1 Hz, 2H), 4.77 – 4.69 (m, 1H), 4.16 – 4.08 (m, 2H), 3.66 (dd, J =8.8, 4.4 Hz, 2H), 2.53 (s, 1H).

[0091] 13 C NMR (101 MHz, CDCl3) δ 165.32, 165.16, 162.88, 162.73, 153.35,153.22, 153.09, 94.76, 94.67, 94.56, 94.48, 93.09, 92.83, 92.57, 62.40,61.49, 31.51, 30.15, 29.71.

[0092] Reaction 2:

[0093]

[0094] 0.1 mmol of 1-bromo-3,5-methoxybenzene (Ⅰ-3) and 0.2 mmol of aziridine-3-ol hydrochloride (Ⅱ-1) were dissolved in a 400 μL reactor, using 0.001 mmol Pd₂(dba)₃ as the transition metal, 0.004 mmol Brettphos as the catalyst, and 0.5 mmol Cs₂CO₃ as the base, at 100 °C. o The mixture was stirred at C for 24 hours, and the reaction was monitored by TLC. Separation by column chromatography yielded a yellow-green solid with a yield of 90% and m / Z 210 [M+H]. + .

[0095] NMR characterization of compound 3 (yellow-green solid):

[0096] 1 H NMR (400 MHz, CDCl3) δ 5.92 (t, J = 2.1 Hz, 1H), 5.63 (d, J = 2.1Hz, 2H), 4.73 – 4.65 (m, 1H), 4.16 – 4.08 (m, 2H), 3.76 (s, 6H), 3.63 (dd, J= 8.4, 4.5 Hz, 2H), 2.34 (s, 1H).

[0097] 13C NMR (101 MHz, CDCl3) δ 161.60, 153.43, 90.77, 90.30, 62.65, 61.75,55.24.

[0098] Reaction 3:

[0099]

[0100] 0.1 mmol of 3-fluoro-5-methylbromobenzene (Ⅰ-4) and 0.2 mmol of azacyclobutane-3-ol hydrochloride (Ⅱ-1) were dissolved in a 400 μL reactor, using 0.001 mmol Pd₂(dba)₃ as the transition metal, 0.004 mmol Brettphos as the catalyst, and 0.5 mmol Cs₂CO₃ as the base, at 100 °C. o The mixture was stirred at C for 24 hours, and the reaction was monitored by TLC. Separation by column chromatography yielded a colorless oily substance with a yield of 90% and a m / Z of 182 [M+H]. + .

[0101] NMR characterization of compound 4 (colorless oily substance):

[0102] 1 H NMR (400 MHz, CDCl3) δ 6.27 (d, J = 9.7 Hz, 1H), 6.04 – 5.91 (m,2H), 4.68 (t, J = 4.8 Hz, 1H), 4.20 – 4.04 (m, 2H), 3.61 (dd, J = 8.5, 4.5Hz, 2H), 2.65 (s, 1H), 2.26 (s, 3H).

[0103] 13 C NMR (101 MHz, CDCl3) δ 165.02, 162.61, 152.89, 152.78, 140.83,140.73, 108.21, 108.19, 105.55, 105.33, 96.36, 96.12, 62.66, 61.75, 21.60,21.58.

[0104] Reaction 4:

[0105]

[0106] 0.1 mmol of 1-bromo-3,5-methylbenzene (Ⅰ-5) and 0.2 mmol of aziridine-3-ol hydrochloride (Ⅱ-1) were dissolved in a 400 μL reactor using 0.001 mmol Pd₂(dba)₃ as the transition metal, 0.004 mmol Brettphos as the catalyst, and 0.5 mmol Cs₂CO₃ as the base. The solution was dissolved at 100 μL. o The mixture was stirred at C for 24 hours, and the reaction was monitored by TLC. Separation by column chromatography yielded a brownish-yellow solid with a yield of 90% and m / Z 178 [M+H]. + .

[0107] NMR characterization of compound 5 (brownish-yellow solid):

[0108] 1 H NMR (400 MHz, CDCl3) δ 6.42 (s, 1H), 6.08 (s, 2H), 4.63 – 4.50 (m,1H), 4.09 – 3.98 (m, 2H), 3.53 (dd, J = 8.2, 4.6 Hz, 2H), 3.41 (d, J = 15.3Hz, 1H), 2.24 (s, 6H).

[0109] 13 C NMR (101 MHz, CDCl3) δ 151.78, 138.74, 120.30, 110.11, 62.72,61.92, 21.54.

[0110] Reaction 5:

[0111]

[0112] 0.1 mmol of 1-bromo-3,5-methylbenzene (Ⅰ-5) and 0.2 mmol of aziridine-3-methyl hydrochloride (Ⅱ-2) were dissolved in a 400 μL reactor using 0.001 mmol Pd₂(dba)₃ as the transition metal, 0.004 mmol Brettphos as the catalyst, and 0.5 mmol Cs₂CO₃ as the base. The solution was dissolved at 100 μL. o The mixture was stirred at C for 24 hours, and the reaction was monitored by TLC. Separation by column chromatography yielded a yellow-green oily substance with a yield of 90% and a m / Z of 176 [M+H]. + .

[0113] NMR characterization of compound 10 (yellow-green oily substance):

[0114] 1H NMR (400 MHz, CDCl3) δ 6.37 (s, 1H), 6.07 (s, 2H), 3.97 (t, J = 7.3Hz, 2H), 3.45 – 3.34 (m, 2H), 2.79 (dt, J = 19.5, 6.7 Hz, 1H), 2.25 (s, 6H),1.25 (d, J = 6.9 Hz, 3H).

[0115] 13 C NMR (101 MHz, CDCl3) δ 152.41, 138.58, 119.27, 109.27, 59.21, 25.34, 21.55, 19.71.

[0116] Reaction Six:

[0117]

[0118] 0.1 mmol of 1-bromo-3,5-methylbenzene (Ⅰ-5) and 0.2 mmol of aziridine-3-methoxyhydrochloride (Ⅱ-3) were dissolved in a 400 μL reactor using 0.001 mmol Pd₂(dba)₃ as the transition metal, 0.004 mmol Brettphos as the catalyst, and 0.5 mmol Cs₂CO₃ as the base. The solution was dissolved at 100 μL. o The mixture was stirred at C for 24 h, and the reaction was monitored by TLC. Separation by column chromatography yielded a yellow-green oily substance with a yield of 90% and m / Z 192 [M+H]. + .

[0119] NMR characterization of compound 15 (yellow-green oily substance):

[0120] 1 H NMR (400 MHz, CDCl3) δ 6.41 (s, 1H), 6.11 (s, 2H), 4.37 – 4.22 (m,1H), 4.06 (dd, J = 7.7, 6.7 Hz, 2H), 3.67 (dd, J = 8.3, 4.6 Hz, 2H), 3.32 (s, 3H), 2.25 (s, 6H).

[0121] 13 C NMR (101 MHz, CDCl3) δ 151.86, 138.65, 119.74, 109.65, 70.12, 58.87, 56.02, 21.51.

[0122] Reaction 7:

[0123]

[0124] 0.1 mmol of 1-bromo-3,5-methylbenzene (Ⅰ-5) and 0.2 mmol of azacyclobutane hydrochloride (Ⅱ-4) were dissolved in a 400 μL reactor, using 0.001 mmol Pd₂(dba)₃ as the transition metal, 0.004 mmol Brettphos as the catalyst, and 0.5 mmol Cs₂CO₃ as the base, at 100 °C. o The mixture was stirred at C for 24 h, and the reaction was monitored by TLC. Separation by column chromatography yielded a yellow-green oily substance with a yield of 90% and a m / Z of 162 [M+H]. + .

[0125] NMR characterization of compound 20 (yellow-green oily substance):

[0126] 1 H NMR (400 MHz, CDCl3) δ 6.39 (s, 1H), 6.09 (s, 2H), 3.83 (t, J = 7.2Hz, 4H), 2.37 – 2.28 (m, 2H), 2.25 (s, 6H).

[0127] 13 C NMR (101 MHz, CDCl3) δ 152.53, 138.57, 119.44, 109.28, 52.50,21.52, 17.04.

[0128] Combination Figure 3 The high-throughput screening results were all excellent. In summary, the present invention, with the support of a high-throughput system, completed the screening of optimal conditions for compounds and the preparation of related compounds, which greatly reduced the time and trial and error costs in the screening process and provided great support for the screening of reaction conditions and the preparation of target compounds.

[0129] Reaction 8

[0130] A method for synthesizing a 1-phenylazine-butane compound is essentially the same as the method described in specific reaction one above, except that the equivalent amounts of the transition metal and catalyst are different. The method includes the following steps:

[0131] 0.1 mmol of 1-bromo-3,5-difluorobenzene (Ⅰ-1) and 0.20 mmol of aziridine-3-ol hydrochloride (Ⅱ-1) were dissolved in a reactor containing 400 μL of DMF, using 0.0005 mmol of Pd₂(dba)₃ as the transition metal, 0.002 mmol of Brettphos as the catalyst, and 0.5 mmol of Cs₂CO₃ as the base, at 100 °C. o The mixture was stirred at C for 24 h, and the reaction was monitored by TLC. After separation by column chromatography, a yellow solid identical to that in reaction one was obtained.

[0132] The following multi-dimensional comparative experiments further validate the above high-throughput results:

[0133] Comparative Example 1

[0134] A method for synthesizing a 1-phenylazacyclobutane compound is essentially the same as the method described in specific reaction one above, except that the feed ratio of the reactants is different. The method includes the following steps:

[0135] 0.1 mmol of 1-bromo-3,5-difluorobenzene (Ⅰ-1) and 0.12 mmol of aziridine-3-ol hydrochloride (Ⅱ-1) were dissolved in a reactor containing 400 μL of DMF. 0.001 mmol of Pd2(dba)3 was used as the transition metal, 0.004 mmol of Brettphos was used as the catalyst, and 0.5 mmol of Cs2CO3 was used as the base. The mixture was stirred at 100 °C for 24 h. The reaction was monitored by TLC and separated by column chromatography to obtain a yellow solid.

[0136] Comparative Example 2

[0137] A method for synthesizing a 1-phenylazacyclobutane compound is essentially the same as the method described in specific reaction one above, except that the feed ratio of the reactants is different. The method includes the following steps:

[0138] 0.1 mmol of 1-bromo-3,5-difluorobenzene (Ⅰ-1) and 0.15 mmol of aziridine-3-ol hydrochloride (Ⅱ-1) were dissolved in a reactor containing 400 μL of DMF. 0.001 mmol of Pd2(dba)3 was used as the transition metal, 0.004 mmol of Brettphos was used as the catalyst, and 0.5 mmol of Cs2CO3 was used as the base. The mixture was stirred at 90 °C for 24 h. The reaction was monitored by TLC and separated by column chromatography to obtain a yellow solid.

[0139] Comparative Example 3

[0140] A method for synthesizing a 1-phenylazacyclobutane compound is essentially the same as the method described in specific reaction one above, except that the reaction temperature is different. It includes the following steps:

[0141] 0.1 mmol of 1-bromo-3,5-difluorobenzene (Ⅰ-1) and 0.20 mmol of aziridine-3-ol hydrochloride (Ⅱ-1) were dissolved in a reactor containing 400 μL of DMF. 0.001 mmol of Pd2(dba)3 was used as the transition metal, 0.004 mmol of Brettphos was used as the catalyst, and 0.5 mmol of Cs2CO3 was used as the base. The mixture was stirred at 110 °C for 24 h. The reaction was monitored by TLC and separated by column chromatography to obtain a yellow solid.

[0142] Comparative Example 4

[0143] A method for synthesizing a 1-phenylazine-butane compound is essentially the same as the method described in specific reaction one above, except that the transition metal involved is different. The method includes the following steps:

[0144] 0.1 mmol of 1-bromo-3,5-difluorobenzene (Ⅰ-1) and 0.20 mmol of aziridine-3-ol hydrochloride (Ⅱ-1) were dissolved in a reactor containing 400 μL of DMF. 0.001 mmol of Pd2(dba)3 was used as the transition metal, 0.004 mmol of Brettphos was used as the catalyst, and 0.5 mmol of Cs2CO3 was used as the base. The mixture was stirred at 100 °C for 24 h. The reaction was monitored by TLC and separated by column chromatography to obtain a yellow solid.

[0145] Comparative Example 5

[0146] A method for synthesizing a 1-phenylazine-butane compound is essentially the same as the method described in specific reaction one above, except that the transition metal involved is different. The method includes the following steps:

[0147] 0.1 mmol of 1-bromo-3,5-difluorobenzene (Ⅰ-1) and 0.20 mmol of aziridine-3-ol hydrochloride (Ⅱ-1) were dissolved in a reactor containing 400 μL of DMF, with 0.001 mmol of Pd₂(dba)₃ as the transition metal, 0.004 mmol of Xantphos as the catalyst, and 0.5 mmol of Cs₂CO₃ as the base, at 100 °C. o The mixture was stirred at C for 24 h, and the reaction was monitored by TLC. The solid was then separated by column chromatography to obtain a yellow solid.

[0148] Comparative Example 6

[0149] A method for synthesizing a 1-phenylazine-butane compound is essentially the same as the method described in specific reaction one above, except that the transition metal involved is different. The method includes the following steps:

[0150] 0.1 mmol of 1-bromo-3,5-difluorobenzene (Ⅰ-1) and 0.20 mmol of azacyclobutane-3-ol hydrochloride (Ⅱ-1) were dissolved in a reactor containing 400 μL of DMF, with 0.001 mmol of Pd₂(dba)₃ as the transition metal, 0.004 mmol of DPEphos as the catalyst, and 0.5 mmol of Cs₂CO₃ as the base, at 100 °C. o The mixture was stirred at C for 24 h, and the reaction was monitored by TLC. The solid was then separated by column chromatography to obtain a yellow solid.

[0151] The yields under different conditions in the above reaction examples and comparative examples are compared as follows:

[0152] 1. Different 1-phenylazacyclobutane compounds were synthesized using different reactants, as shown in Table 1.

[0153]

[0154] As shown in Table 1, when the substituents of the compound represented by Formula I are selected from methyl and methoxy groups, the product yield is 90%, which is relatively high. When the substituents of the compound represented by Formula II are selected from methoxy and H groups, the product yield is also 90%, which is relatively high.

[0155] 2. The reaction conditions with different feed ratios under the same reaction raw materials are shown in Table 2.

[0156]

[0157] As shown in Table 2, when the amount of compound II-1 fed is 0.1-0.15 mmol, the product yield reaches 60-75%, especially when the amount of compound II-1 fed is 0.15-0.2 mmol, the product yield reaches 75-88%, which is relatively high.

[0158] 3. The reaction conditions at different reaction temperatures are shown in Table 3.

[0159]

[0160] As can be seen from the results in Table 3, when the reaction temperature is 90~110℃ and the reaction time is 24h, the product yield can reach 80~88%, which is relatively high.

[0161] 4. The reaction conditions under different catalysts are shown in Table 4.

[0162]

[0163] As shown in Table 4, the product yield was 10-20% when the catalysts were Xantphos and DPEphos, and 88% when the catalyst was Brettphos, which is relatively high.

[0164] 5. The reaction conditions under different transition metal and catalyst equivalents are shown in Table 5.

[0165]

[0166] As shown in Table 5, when the equivalent ratio of transition metal to catalyst is 1:0.005:0.02, the product yield is only 55%, while when the equivalent ratio of transition metal to catalyst is 1:0.01:0.04, the product yield is 88%, which is relatively high.

[0167] In summary, the present invention uses inexpensive haloalkanes and N-heterocyclic amines as raw materials under the action of a metal catalyst. First, the active metal undergoes oxidative addition with the haloalkanes, then undergoes transmetalation with the amines, and finally undergoes reductive elimination to obtain the target product. At the same time, salt and active metal are produced to complete the catalytic cycle.

[0168] When the substituents of the compound represented by Formula I are selected from methyl and methoxy, and the substituents of the compound represented by Formula II are selected from methoxy and H, and the amount of compound II-1 fed is 0.15~0.2 mmol, the reaction temperature is 90~110 ℃, and the reaction time is 24 h, the product yield is relatively high.

[0169] Based on the above-described preferred embodiments of the present invention, those skilled in the art can make various changes and modifications without departing from the inventive concept, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for high-throughput synthesis of 1-phenylazacyclobutane compounds, characterized in that, Includes the following steps: ； In a solvent, the compound shown in Formula I and the compound shown in Formula II undergo a CN coupling reaction in the presence of a catalyst, a base and a transition metal at 100 °C to give the 1-phenylazacyclobutane compound shown in Formula III. The compound shown in Formula I is selected from any one of the following compounds: ； The compound shown in Formula II is selected from any one of the following compounds: ； The compound shown in Formula III is selected from any one of the following compounds: ； The catalyst used is BrettPhos, the solvent is DMF, the transition metal is Pd2(dba)3, and the base is Cs2CO3. The ratio of the compound shown in Formula I to the compound shown in Formula II, the transition metal, the catalyst, and the base is 1:2:0.01:0.04:

5.

2. The method for high-throughput synthesis of 1-phenylazacyclobutane compounds according to claim 1, characterized in that, The method includes: (a) supplying each of a plurality of reaction chambers with a compound of formula I or II, a base, a solvent, a transition metal, and a catalyst; (b) maintaining the plurality of reaction chambers under conditions suitable for the formation of a compound of formula III; (c) simultaneously purifying the plurality of compounds of formula III; and (d) evaluating one or more physicochemical properties of the purified compound III.

3. The method for high-throughput synthesis of 1-phenylazacyclobutane compounds according to claim 2, characterized in that, The multiple reaction chambers are independent of each other and are set in metal holes in a parallel reactor. The bottom of the parallel reactor has a first rubber pad for supporting the reaction flasks, and the top is provided with a metal cover. A second rubber pad is provided between the metal cover and the reaction flasks, and a buffer film is provided between the second rubber pad and the reaction flasks.

4. The method for high-throughput synthesis of 1-phenylazine-butane compounds according to claim 3, characterized in that, The method also includes simultaneously heating and stirring multiple reaction flasks using a heating stirrer after the reactants are added to the reaction flasks; and simultaneously rotary evaporating the multiple reaction flasks using a centrifugal rotary evaporator after the reaction is completed.

5. The method for high-throughput synthesis of 1-phenylazine butane compounds according to claim 4, characterized in that, a base is first added to the reaction flask, followed by a magnetic stir bar and compounds of formula I and II as substrates, as well as a catalyst, and finally a transition metal is added; and each material is added simultaneously to all reaction flasks at once through an auxiliary storage tank.

6. The method for high-throughput synthesis of 1-phenylazacyclobutane compounds according to claim 4 or 5, characterized in that, The heating stirrer supports the reaction flask via a metal tray and controls the reaction speed to be 600-700 revolutions per minute.

7. The method for high-throughput synthesis of 1-phenylheterocyclic butane compounds according to claim 1, characterized in that, The reaction time for CN coupling is 12-24 h.

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