Method for high-throughput synthesis of 1-phenyl azetidine compound

Abstract

The invention discloses a method for high-flux synthesis of 1-phenyl azetidine compounds, which comprises the following steps: carrying out C-N coupling reaction on # imgabs0 # in a solvent, a compound as shown in a formula I and a compound as shown in a formula II in the presence of a catalyst and alkali to obtain the 1-phenyl azetidine compounds as shown in a formula III, in the formula, R1 and R2 are any one of alkyl, halogen, aryl, substituted aryl, alkoxy, hydroxyl and nitrile group; r3 is any one of F, Cl, Br and I; and R4 is any one of hydroxyl, alkyloxy, H, halogen and alkyl. A series of nitrogen heterocyclic compounds are constructed through high-throughput synthesis, a series of nitrogen heterocyclic compounds are obtained, and optimal reaction conditions are obtained within extremely short time through proper high-throughput screening; the problems that an existing synthesis method for constructing the carbon-nitrogen heterocyclic ring is complex, condition selection is difficult, and labor and time cost is high can be solved.

Description

Technical Field

[0001] The present invention relates to the field of nitrogen heterocyclic compounds, and in particular to a method for high-throughput synthesis of 1-phenylazetidine compounds. Background Art

[0002] N-aryl heterocycles are of great importance to life because their structural subunits are found in many natural products. They are one of the most common structural features occurring in biologically active compounds and are widely used throughout the chemical industry as essential intermediates or additives for the preparation of drugs, herbicides, dyes, and many other compounds.

[0003] Chinese patent document CN101747249A discloses 1-benzhydryl-3-aminoazetidine (D) or 1-benzhydryl-3-hydroxy-3-aminomethylazetidine (I), and the two azetidines obtained can be used in the synthesis of anti-tumor and anti-inflammatory drugs as synthetic intermediates. However, the reaction steps of the synthesis are relatively complicated, and there is a large room for improvement in the reaction efficiency. Summary of the invention

[0004] In view of the problems existing in the above-mentioned prior art, in order to solve the problems that the existing synthesis methods are relatively complicated to construct carbon-nitrogen heterocycles, the selection of conditions is relatively difficult, and the manpower and time costs are relatively high, the present invention constructs a series of nitrogen heterocyclic compounds through high-throughput synthesis, obtains a series of nitrogen heterocyclic compounds, and obtains the best reaction conditions in a very short time through appropriate high-throughput screening.

[0005] To achieve one of the above purposes, a method for high-throughput synthesis of 1-phenylazetidine compounds is provided. The present invention adopts the following technical solution:

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

[0007]

[0008] In a solvent, the compound represented by formula I and the compound represented by formula II undergo CN coupling reaction in the presence of a catalyst and a base to obtain a 1-phenylazetidine compound represented by formula III;

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

[0010] Preferably, the method comprises: (a) providing a compound of formula I or formula II, a base, a solvent, a transition metal, and a catalyst to each reaction chamber in a plurality of reaction chambers; (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 physical and chemical 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 base is selected from DIPEA, Et3N, DBU, DBN, potassium tert-butoxide, sodium tert-butoxide, potassium phosphate, cesium carbonate, potassium carbonate, cesium fluoride, potassium acetate, 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, allylpalladium chloride dimer, and Brettphos-Pd-G3.

[0015] Preferably, the multiple reaction chambers adopt multiple independent reaction bottles (each reaction bottle serves as an independent reaction chamber) arranged in metal holes in a parallel reactor, the parallel reactor has a first rubber pad for supporting the reaction bottle at the bottom, a metal cover is provided on the top, a second rubber pad is provided between the metal cover and the reaction bottle, and a buffer film is provided between the second rubber pad and the reaction bottle.

[0016] Furthermore, the method also includes using a heating agitator to synchronously heat and stir multiple reaction bottles after the reactants are added to the reaction bottles; and after the reaction is completed, using a centrifugal rotary evaporator to synchronously rotary evaporate the multiple reaction bottles.

[0017] Furthermore, the inorganic base is first added to the reaction bottle, followed by the magnetic stirrer, substrate and catalyst, and finally the transition metal; and each material is added to all reaction bottles at the same time through the auxiliary liquid storage tank.

[0018] Furthermore, the heating stirrer supports the reaction bottle via a metal tray; and the reaction speed is controlled to be 600-700 rpm via a magnetic stirrer.

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

[0020] Furthermore, the ratio of the compound represented by formula I to the compound represented by 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] Although screening reaction conditions and synthesizing related compounds can be achieved through traditional chemical methods, due to the long development time and high cost, and usually only specific solutions can be provided, and solutions for multiple compounds cannot be obtained at the same time. The current synthesis method involves a slow process of changing and trying to optimize each reaction parameter in turn. This may include the type and concentration of substrates, bases and transition metals and the type and equivalent of transition metals, the type of solvent and purification steps. This gradual change of reaction parameters will lead to long-term comprehensive trials and errors, which in turn makes the optimization of conditions more laborious. Compared with traditional technologies, the beneficial effects of the present invention are:

[0023] 1) The present invention provides a complex high-throughput screening scheme for multiple compounds, screens the reaction substances based on appropriate solvents, transition metals, types and equivalents of transition metals, bases and equivalents of substrates, and fully exerts the best catalytic reaction performance in the reaction system, thereby synthesizing the target compound.

[0024] 2) The present invention provides a solution for high-throughput screening and synthesis of compounds by using a high-throughput system based on a parallel reactor, a heating stirrer, and a centrifugal rotary evaporator, which can quickly feed and change reaction conditions, and is used to quickly screen reaction conditions and synthesize target compounds. The properties of the high-throughput system can solve the arduous process of changing multiple parameters, and it has been verified through experiments that the reaction based on high-throughput screening of the present invention has the characteristics of high yield and simple and convenient reaction. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The present invention is further described below in conjunction with the accompanying drawings and embodiments.

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

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

[0028] Figure 3 The diagram shows the high-throughput synthesis system of series compounds III. DETAILED DESCRIPTION

[0029] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually performed under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used in the text have the same meanings as those familiar to those skilled in the art. In addition, any method and material similar or equivalent to the described content can be applied to the method of the present invention. The preferred implementation methods and materials described in the text are for demonstration purposes only.

[0030] The solvents used in the present invention are all analytically pure. The materials used as raw materials in the examples are all purchased.

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

[0032]

[0033] In a solvent, the compound represented by formula I and the compound represented by formula II undergo CN coupling reaction in the presence of a catalyst and a base to obtain a 1-phenylazetidine compound represented by formula III;

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

[0035] Specifically, the method comprises: (a) providing compounds of formula I and formula II, a base, a solvent, a transition metal, and a catalyst to each reaction chamber in a plurality of reaction chambers; (b) maintaining the plurality of reaction chambers under conditions suitable for forming compounds of formula III; (c) purifying the plurality of compounds of formula III simultaneously; and (d) evaluating one or more physical and chemical properties of the purified compound III.

[0036] The present invention is based on the following reaction principle: under the action of transition metal, the following processes are carried out: first, the active metal undergoes oxidative addition with the halogenated hydrocarbon, then coordinates with the amine to undergo transmetallation, and finally undergoes reduction elimination to obtain the target product, while producing salt and active metal to complete the catalytic cycle; since the coupling reaction has high requirements for the specific structure of the catalyst, often a certain catalyst has a good catalytic effect only on a certain type of reaction, high-throughput screening can quickly compare the synthesis conditions of multiple catalysts for multiple substrates under different combinations of transition metals, bases, and solvents; in order to give full play to the synergistic effect of the above mechanism, it is preferred to perform further high-throughput screening based on the following reactants to obtain the best reaction conditions:

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

[0038] The base 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 solvent is 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, allylpalladium chloride dimer, and Brettphos-Pd-G3.

[0041] In order to quickly and accurately obtain high-throughput reaction conditions, the present invention performs the high-throughput reaction based on a high-throughput system, which includes a parallel reactor, a centrifugal evaporator, and a heating stirrer:

[0042] The multiple reaction chambers use multiple reaction bottles that are independent of each other and completely set in the metal holes in the parallel reactor. The bottom of the parallel reactor has a first rubber pad for supporting the reaction bottle, and the top is provided with a metal cover. A second rubber pad is provided between the metal cover and the reaction bottle, and a buffer film is provided between the second rubber pad and the reaction bottle. At this point, the second rubber pad of the top reaction bottle can ensure the sealing of the reaction, and because the reaction bottle is completely wrapped by the metal hole, the periphery of the first rubber pad at the bottom and the bottom are all wrapped by metal, so the heat transfer effect in each reaction chamber of the parallel reactor is good.

[0043] The plurality of reaction chambers are on a single plate 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] In addition, the heating stirrer supports the reaction bottle through a metal tray, which can better ensure the heat transfer efficiency between the heater and the reactor, and ensure the stability of the reaction temperature. The reaction liquid is wrapped by the heated metal, avoiding the temperature difference between the upper and lower reaction liquids.

[0045] After the reactants are added to the reaction bottles, multiple reaction bottles are heated and stirred synchronously using a heating stirrer; and after the reaction is completed, the multiple reaction bottles are synchronously rotary evaporated using a centrifugal rotary evaporator. In implementing 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 a high-throughput screening reaction based on the high-throughput system, an inorganic base is first added to the reaction bottle, followed by a magnetic stirrer, a substrate, and a catalyst, and finally a transition metal. Based on this, when the solvent is rotary evaporated, the magnetic stirrer is prevented from being stuck to the bottom of the reaction bottle by the material. Each material is added to all reaction bottles at once through an auxiliary liquid storage tank, thereby ensuring the timeliness and uniformity of the addition.

[0047] When performing high-throughput screening, the reaction speed is controlled to be 600-700 rpm, preferably 660 rpm. Too low a speed may easily lead to insufficient stirring of the edge reactor, while too high a speed may lead to excessive stirring, causing the reaction liquid to splash onto the plastic film and increase mutual contamination between materials.

[0048] Based on the above embodiment, the present invention selects the following substrates to carry out the following specific tests:

[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] The product compound III is selected from any one of the following compounds:

[0054]

[0055]

[0056] Example 1

[0057] From the perspective of the adaptability of the CN coupling reaction, the present invention selects some raw materials with better adaptability for the reaction.

[0058] Transfer a 96-well plate (a parallel reactor has 96 independent metal holes, each of which has 96 reaction bottles. A1, A2...A12...B1, B2...B12...H1, H2...H12 in the text are the numbers of each hole of the 96-well plate, and the ellipsis is the number arranged in sequence according to the combination of letter row numbers and number column numbers) to a glove box, first add an inorganic base to the reaction bottle, then add a magnetic stirrer, substrate and catalyst, and finally add a transition metal, and each material is added to all reaction bottles at the same time through an auxiliary liquid storage tank. The specific materials are:

[0059] Catalyst: add 0.01mmol RuPhos to A1-H1 respectively, add 0.01mmol XPhos to A2-H2 respectively, add 0.005mmol BINAP to A3-H3 respectively, add 0.01mmol XantPhos to A4-H4 respectively, add 0.01mmol APhos to A5-H5 respectively, add 0.005mmol DPEPhos to A6-H6 respectively, add 0.01mmol BrettPhos to A7-H7 respectively, add 0.01mmol PPh3 to A8-H8 respectively, add 0.01mmol PCy3 to A9-H9 respectively, add 0.005mmol DPPP to A10-H10 respectively, add 0.01mmol CyJhonPhos to A11-H11 respectively, and add 0.01mmol DavePhos to A12-H12 respectively;

[0060] Transition metal: add 0.005mmol Pd(OAc)2 to A1-A12, B1-B12, E1-E12, and F1-F12, respectively; add 0.0025mmol Pd2(dba)3 to C1-C12, D1-D12, G1-G12, and H1-H12, respectively;

[0061] Substrate: Add 0.1mmol Ⅰ-1 to A1-A12, B1-B12, C1-C12, D1-D12, E1-E12, F1-F12, G1-G12, and H1-H12 respectively; add 0.15mmol Ⅱ-1 to A1-A12, B1-B12, C1-C12, D1-D12, E1-E12, F1-F12, G1-G12, and H1-H12 respectively;

[0062] Base: 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;

[0063] Solvent: add 400uL DMF to A1-A12, B1-B12, C1-C12, and D1-D12 respectively, and add 400uL DMSO to E1-E12, F1-F12, G1-G12, and H1-H12 respectively.

[0064] After the feeding is completed, the reactor is sealed, the reactor is transferred out of the glove box, and the reaction is placed at 100° C. for 24 hours.

[0065] 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 determined to be Pd2(dba)3, and the base was Cs2CO3.

[0066] Example 2

[0067] Based on the results of Example 1, high-throughput screening was further performed (A1, A2...A5...B1, B2...B5...E1, E2...E5 in the text are the numbers of each well of the multi-well plate, and the ellipsis is the number arranged in sequence according to the combination of letter row number and number column number). Since at least 2.0eq of base is required in the metal coupling reaction process, and reactant II is hydrochloride, more base needs to be added to allow the reaction to proceed, so the equivalent of the base is not carefully screened.

[0068] The reactor was transferred into a glove box;

[0069] Add 0.12 mmol of II-1 to A1-A5 and B1-B5, add 0.2 mmol of II-1 to C1-C5 and D1-D5, and add 0.15 mmol of II-1 to E1-E5;

[0070] Add 0.1 mmol Ⅰ-1 to A1-A5, B1-B5, C1-C5, D1-D5, and E1-E5 respectively;

[0071] 0.001 mmol Pd2(dba)3 was added to A1-A5 and C1-C5, and 0.0005 mmol Pd2(dba)3 was added to B1-B5 and D1-D5, respectively;

[0072] 0.004 mmol BrettPhos was added to A1-A5 and C1-C5, and 0.002 mmol BrettPhos was added to B1-B5 and D1-D5, respectively;

[0073] 0.3 mmol Cs2CO3 was added to A1-D1, 0.5 mmol Cs2CO3 was added to A2-H2, 0.4 mmol sodium tert-butoxide was added to A3-D3, 0.4 mmol CsF was added to A4-D4, and 0.4 mmol K2CO3 was added to A5-D5;

[0074] Add 400uL DMF to A1-A5, B1-B5, C1-C5, D1-D5, and E1-E5 respectively;

[0075] After the feeding is completed, the reactor is sealed, the reactor is transferred out of the glove box, and the reaction is placed at 100° C. for 24 hours.

[0076] After screening in Example 2, a better compounding ratio was obtained, and the ratio of the compound of formula I to the compound of formula II, transition metal, catalyst, and base was 1:(1-2):(0.005-0.01):(0.02-0.04):(3-5).

[0077] In addition, it should be noted that since the high-throughput system sampling requires opening the reactor, the reaction system is easily affected by air, resulting in catalyst deactivation, so based on the research on the CN coupling reaction mechanism, a more stable reaction time was selected for high-throughput screening. In addition, because the reaction temperature of the high-throughput system can only be unified, the screening of the reaction temperature does not involve high-throughput screening.

[0078] Example 3

[0079] Based on the results of Examples 1 and 2, the best combination of transition metals, transition metals, catalysts and solvents is selected to prepare the relevant compounds. Example 3 mainly demonstrates the preparation of some compounds (the specific reaction steps of each compound will be listed in detail later).

[0080] The reactor was transferred into a glove box;

[0081] Add 0.1 mmol of I-1 to A1-D1 and

[0082] Add Ⅰ-2 0.1mmol to A2-D2, add Ⅰ-3 0.1mmol to A3-D3, add Ⅰ-4 0.1mmol to A4-D4, add Ⅰ-5 0.1mmol to A5-D5;

[0083] Add 0.2 mmol of II-1 to A1-A5, 0.2 mmol of II-2 to B1-B5, 0.2 mmol of II-3 to C1-C5, and 0.2 mmol of II-4 to D1-D5;

[0084] Add 0.001mmol Pd2(dba)3 to A1-A5, B1-B5, C1-C5, and D1-D5, respectively; add 0.004mmol Brettphos to A1-A5, B1-B5, C1-C5, and D1-D5, respectively; add 0.5mmol Cs2CO3 to A1-A5, B1-B5, C1-C5, and D1-D5, respectively; add 400uL DMF to A1-A5, B1-B5, C1-C5, and D1-D5, respectively;

[0085] After the feeding is completed, the reactor is sealed, the reactor is transferred out of the glove box, and the reaction is placed at 100° C. for 24 hours.

[0086] After the reaction was completed, some compounds were obtained through high-throughput preparation. The specific reaction information is as follows:

[0087] Reaction 1:

[0088]

[0089] 0.1mmol 1-bromo-3,5-difluorobenzene (I-1) and 0.2mmol azetidine-3-ol hydrochloride (II-1) were dissolved in a reactor containing 400uL DMF, 0.001mmol Pd2(dba)3 was used as transition metal, 0.004mmol Brettphos was used as catalyst, 0.5mmol Cs2CO3 was used as base, stirred at 100℃ for 24h, the reaction was monitored by TLC, and separated by column chromatography to obtain a yellow solid with a yield of 88%, m / Z186[M+H] + .

[0090] NMR characterization of compound 1 (yellow solid):

[0091] 1 H NMR (400MHz, CDCl3) δ6.16 (tt, J=9.3, 2.2Hz, 1H), 5.90 (dd, J=9.6, 2.1Hz, 2H), 4.77–4.69(m,1H),4.16–4.08(m,2H),3.66(dd,J=8.8,4.4Hz,2H),2.53(s,1H).

[0092] 13C NMR (101MHz, CDCl3) δ165.32,165.16,162.88,162.73,153.35,153.22,153.09,94 .76,94.67,94.56,94.48,93.09,92.83,92.57,62.40,61.49,31.51,30.15,29.71.

[0093] Reaction 2:

[0094]

[0095] 0.1mmol 1-bromo-3,5-methoxybenzene (I-3) and 0.2mmol azetidine-3-ol hydrochloride (II-1) were dissolved in a 400uL reactor, 0.001mmol Pd2(dba)3 was used as transition metal, 0.004mmol Brettphos was used as catalyst, 0.5mmol Cs2CO3 was used as base, stirred at 100℃ for 24h, the reaction was monitored by TLC, and separated by column chromatography to obtain a yellow-green solid with a yield of 90%, m / Z 210[M+H] + .

[0096] NMR characterization of compound 3 (yellow-green solid):

[0097] 1 H NMR(400MHz, CDCl3)δ5.92(t,J=2.1Hz,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=8.4,4.5Hz,2H),2.34(s,1H).

[0098] 13 C NMR (101MHz, CDCl3) δ161.60,153.43,90.77,90.30,62.65,61.75,55.24.

[0099] Reaction three:

[0100]

[0101] 0.1mmol 3-fluoro-5-methylbromobenzene (I-4) and 0.2mmol azetidine-3-ol hydrochloride (II-1) were dissolved in a 400uL reactor, 0.001mmol Pd2(dba)3 was used as transition metal, 0.004mmol Brettphos was used as catalyst, 0.5mmol Cs2CO3 was used as base, stirred at 100℃ for 24h, the reaction was monitored by TLC, and separated by column chromatography to obtain a colorless oil with a yield of 90%, m / Z182[M+H] + .

[0102] NMR characterization of compound 4 (colorless oil):

[0103] 1 H NMR(400MHz, CDCl3)δ6.27(d,J=9.7Hz,1H),6.04–5.91(m,2H),4.68(t,J=4.8Hz ,1H),4.20–4.04(m,2H),3.61(dd,J=8.5,4.5Hz,2H),2.65(s,1H),2.26(s,3H).

[0104] 13 C NMR (101MHz, CDCl3) δ165.02,162.61,152.89,152.78,140.83,140.73,10 8.21,108.19,105.55,105.33,96.36,96.12,62.66,61.75,21.60,21.58.

[0105] Reaction 4:

[0106]

[0107] 0.1mmol 1-bromo-3,5-methylbenzene (I-5) and 0.2mmol azetidine-3-ol hydrochloride (II-1) were dissolved in a 400uL reactor, 0.001mmol Pd2(dba)3 was used as transition metal, 0.004mmol Brettphos was used as catalyst, 0.5mmol Cs2CO3 was used as base, stirred at 100℃ for 24h, the reaction was monitored by TLC, and separated by column chromatography to obtain a brown-yellow solid with a yield of 90%, m / Z178[M+H] + .

[0108] NMR characterization of compound 5 (brown solid):

[0109] 1H NMR(400MHz, CDCl3)δ6.42(s,1H),6.08(s,2H),4.63–4.50(m,1H),4.09–3. 98(m,2H),3.53(dd,J=8.2,4.6Hz,2H),3.41(d,J=15.3Hz,1H),2.24(s,6H).

[0110] 13 C NMR (101MHz, CDCl3) δ151.78,138.74,120.30,110.11,62.72,61.92,21.54.

[0111] Reaction 5:

[0112]

[0113] 0.1mmol 1-bromo-3,5-methylbenzene (I-5) and 0.2mmol azetidine-3-methyl hydrochloride (II-2) were dissolved in a 400uL reactor, 0.001mmol Pd2(dba)3 was used as transition metal, 0.004mmol Brettphos was used as catalyst, 0.5mmol Cs2CO3 was used as base, stirred at 100℃ for 24h, the reaction was monitored by TLC, and separated by column chromatography to obtain a yellow-green oil with a yield of 90%, m / Z 176[M+H] + .

[0114] NMR characterization of compound 10 (yellow-green oil):

[0115] 1 H NMR (400MHz, CDCl3) δ6.37 (s, 1H), 6.07 (s, 2H), 3.97 (t, J = 7.3Hz, 2H), 3.45–3 .34(m,2H),2.79(dt,J=19.5,6.7Hz,1H),2.25(s,6H),1.25(d,J=6.9Hz,3H).

[0116] 13 C NMR (101MHz, CDCl3) δ152.41,138.58,119.27,109.27,59.21,25.34,21.55,19.71.

[0117] Reaction 6:

[0118]

[0119] 0.1mmol 1-bromo-3,5-methylbenzene (I-5) and 0.2mmol azetidine-3-methoxy hydrochloride (II-3) were dissolved in a 400uL reactor, 0.001mmol Pd2(dba)3 was used as transition metal, 0.004mmol Brettphos was used as catalyst, 0.5mmol Cs2CO3 was used as base, stirred at 100℃ for 24h, the reaction was monitored by TLC, and separated by column chromatography to obtain a yellow-green oil with a yield of 90%, m / Z 192[M+H] + .

[0120] NMR characterization of compound 15 (yellow-green oil):

[0121] 1 H NMR (400MHz, CDCl3) δ6.41(s,1H),6.11(s,2H),4.37–4.22(m,1H),4.06(dd,J=7.7,6.7Hz,2H),3.67(dd,J=8.3,4.6Hz,2H),3.32(s,3H),2.25(s,6H).

[0122] 13 C NMR (101MHz, CDCl3) δ151.86,138.65,119.74,109.65,70.12,58.87,56.02,21.51.

[0123] Reaction 7:

[0124]

[0125] 0.1mmol 1-bromo-3,5-methylbenzene (I-5) and 0.2mmol azetidine hydrochloride (II-4) were dissolved in a 400uL reactor, 0.001mmol Pd2(dba)3 was used as transition metal, 0.004mmol Brettphos was used as catalyst, 0.5mmol Cs2CO3 was used as base, stirred at 100℃ for 24h, the reaction was monitored by TLC, and separated by column chromatography to obtain a yellow-green oil with a yield of 90%, m / Z162[M+H] + .

[0126] NMR characterization of compound 20 (yellow-green oil):

[0127] 1 H NMR (400MHz, CDCl3) δ6.39 (s, 1H), 6.09 (s, 2H), 3.83 (t, J = 7.2Hz, 4H), 2.37–2.28 (m, 2H), 2.25 (s, 6H).

[0128] 13 C NMR (101MHz, CDCl3) δ152.53,138.57,119.44,109.28,52.50,21.52,17.04.

[0129] Combination Figure 3 The high-throughput screening results are all relatively excellent. From the above analysis, it can be seen that the present invention, with the support of the high-throughput system, completes the screening of the optimal conditions for compounds and the preparation of related compounds, which greatly reduces the time and trial-and-error costs in screening, and provides great support for the screening of reaction conditions and the preparation of target compounds.

[0130] Reaction 8

[0131] A method for synthesizing 1-phenylazetidine compounds is basically the same as the method of the above-mentioned specific reaction 1, except that the reaction transition metal and catalyst equivalents are different. It includes the following steps:

[0132] 0.1mmol 1-bromo-3,5-difluorobenzene (Ⅰ-1) and 0.20mmol azetidine-3-ol hydrochloride (Ⅱ-1) were dissolved in a reactor containing 400uL DMF, with 0.0005mmol Pd2(dba)3 as transition metal, 0.002mmol Brettphos as catalyst, 0.5mmol Cs2CO3 as base, stirred at 100℃ for 24h, the reaction was monitored by TLC, and separated by column chromatography to obtain a yellow solid identical to reaction 1.

[0133] The following multi-dimensional comparative experiments further verify the above high-throughput results:

[0134] Comparative Example 1

[0135] A method for synthesizing 1-phenylazetidine compounds is basically the same as the method of the above-mentioned specific reaction 1, except that the feed ratio of the reaction raw materials is different. It includes the following steps:

[0136] 0.1mmol 1-bromo-3.5-difluorobenzene (Ⅰ-1) and 0.12mmol azetidine-3-ol hydrochloride (Ⅱ-1) were dissolved in a reactor containing 400uL DMF, with 0.001mmol Pd2(dba)3 as transition metal, 0.004mmol Brettphos as catalyst, 0.5mmol Cs2CO3 as base, stirred at 100℃ for 24h, the reaction was monitored by TLC, and separated by column chromatography to obtain a yellow solid.

[0137] Comparative Example 2

[0138] A method for synthesizing 1-phenylazetidine compounds is basically the same as the method of the above-mentioned specific reaction 1, except that the feed ratio of the reaction raw materials is different. It includes the following steps:

[0139] 0.1mmol 1-bromo-3,5-difluorobenzene (Ⅰ-1) and 0.15mmol azetidine-3-ol hydrochloride (Ⅱ-1) were dissolved in a reactor containing 400uL DMF, with 0.001mmol Pd2(dba)3 as transition metal, 0.004mmol Brettphos as catalyst, 0.5mmol Cs2CO3 as base, stirred at 90℃ for 24h, the reaction was monitored by TLC, and separated by column chromatography to obtain a yellow solid.

[0140] Comparative Example 3

[0141] A method for synthesizing 1-phenylazetidine compounds is basically the same as the method of the above-mentioned specific reaction 1, except that the reaction temperature is different. It comprises the following steps:

[0142] 0.1mmol 1-bromo-3,5-difluorobenzene (Ⅰ-1) and 0.20mmol azetidine-3-ol hydrochloride (Ⅱ-1) were dissolved in a reactor containing 400uL DMF, with 0.001mmol Pd2(dba)3 as transition metal, 0.004mmol Brettphos as catalyst, 0.5mmol Cs2CO3 as base, stirred at 110℃ for 24h, the reaction was monitored by TLC, and separated by column chromatography to obtain a yellow solid.

[0143] Comparative Example 4

[0144] A method for synthesizing 1-phenylazetidine compounds is basically the same as the method of the above-mentioned specific reaction 1, except that the reaction transition metal is different. It comprises the following steps:

[0145] 0.1mmol 1-bromo-3,5-difluorobenzene (Ⅰ-1) and 0.20mmol azetidine-3-ol hydrochloride (Ⅱ-1) were dissolved in a reactor containing 400uL DMF, with 0.001mmol Pd2(dba)3 as transition metal, 0.004mmol Brettphos as catalyst, 0.5mmol Cs2CO3 as base, stirred at 100℃ for 24h, the reaction was monitored by TLC, and separated by column chromatography to obtain a yellow solid.

[0146] Comparative Example 5

[0147] A method for synthesizing 1-phenylazetidine compounds is basically the same as the method of the above-mentioned specific reaction 1, except that the reaction transition metal is different. It comprises the following steps:

[0148] 0.1mmol 1-bromo-3,5-difluorobenzene (Ⅰ-1) and 0.20mmol azetidine-3-ol hydrochloride (Ⅱ-1) were dissolved in a reactor containing 400uL DMF, with 0.001mmol Pd2(dba)3 as transition metal, 0.004mmol Xantphos as catalyst, 0.5mmol Cs2CO3 as base, stirred at 100℃ for 24h, the reaction was monitored by TLC, and separated by column chromatography to obtain a yellow solid.

[0149] Comparative Example 6

[0150] A method for synthesizing 1-phenylazetidine compounds is basically the same as the method of the above-mentioned specific reaction 1, except that the reaction transition metal is different. It comprises the following steps:

[0151] 0.1mmol 1-bromo-3,5-difluorobenzene (Ⅰ-1) and 0.20mmol azetidine-3-ol hydrochloride (Ⅱ-1) were dissolved in a reactor containing 400uL DMF, with 0.001mmol Pd2(dba)3 as transition metal, 0.004mmol DPEphos as catalyst, 0.5mmol Cs2CO3 as base, stirred at 100℃ for 24h, the reaction was monitored by TLC, and separated by column chromatography to obtain a yellow solid.

[0152] The yields under different conditions in the above reaction examples and comparative examples are compared as follows:

[0153] 1. Different 1-phenylazetidine compounds were synthesized using different reaction raw materials, see Table 1.

[0154] Table 1. Raw materials and products of the above reactions 1 to 7

[0155]

[0156]

[0157] From the results in Table 1, it can be seen that when the substituents of the compound represented by Formula I are selected from methyl and methoxy, 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, the product yield is 90%, which is relatively high.

[0158] 2. The reaction conditions with different feed ratios under the same reaction raw materials are shown in Table 2.

[0159] Table 2 Reaction of different feed ratios

[0160]

[0161] From the results in Table 2, it can be seen that when the feed amount of compound II-1 is 0.1-0.15 mmol, the product yield reaches 60-75%, especially when the feed amount of compound II-1 is 0.15-0.2 mmol, the product yield reaches 75-88%, and the product yield is relatively high.

[0162] 3. The reaction conditions at different reaction temperatures are shown in Table 3.

[0163] Table 3 Reaction conditions at different reaction temperatures

[0164]

[0165] From the results in Table 3, it can be seen that when the reaction temperature is 90-110° C. and the reaction time is 24 h, the product yield can reach 80-88%, which is relatively high.

[0166] 4. The reaction conditions under different catalysts are shown in Table 4.

[0167] Table 4 Reaction conditions under different catalysts

[0168]

[0169] From the results in Table 4, it can be seen that when the catalyst is Xantphos and DPEphos, the product yield is 10-20%, and when the catalyst is Brettphos, the product yield is 88%, and the product yield is relatively high.

[0170] 5. The reaction conditions under different transition metal and catalyst equivalents are shown in Table 5.

[0171] Table 4 Reaction conditions under different catalysts

[0172]

[0173] From the results in Table 5, it can be seen that when the transition metal and catalyst equivalents are 1:0.005:0.02, the product yield is only 55%, and when the transition metal and catalyst equivalents are 1:0.01:0.04, the product yield is 88%, and the product yield is relatively high.

[0174] From the above analysis, it can be seen that the present invention uses cheap halogenated hydrocarbons and N-heterocyclic amines as raw materials under the action of metal catalysts. First, the active metal undergoes oxidative addition with the halogenated hydrocarbon, then coordinates with the amine to undergo transmetallation, and finally obtains the target product through reduction elimination, while producing salt and active metal to complete the catalytic cycle.

[0175] When the substituent of the compound represented by formula I is selected from methyl and methoxy, and the substituent of the compound represented by formula II is selected from methoxy and H, the feeding amount of compound II-1 is 0.15-0.2 mmol, the reaction temperature is 90-110°C, and the reaction time is 24h, the product yield is relatively high.

[0176] The above-mentioned ideal embodiments of the present invention are inspirations. Through the above-mentioned description content, relevant personnel can make various changes and modifications without departing from the technical idea of ​​the present invention. These equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for high-throughput synthesis of 1-phenylazetidine compounds, characterized in that: The steps include: In a solvent, the compound represented by formula I and the compound represented by formula II undergo CN coupling reaction in the presence of a catalyst and a base to obtain a 1-phenylazetidine compound represented by formula III; In the formula, R1 and R2 are any one of alkyl, halogen, aryl, substituted aryl, alkoxy, hydroxyl, and nitrile; R3 is any one of F, Cl, Br, and I; R4 is any one of hydroxyl, alkyloxy, H, halogen, and alkyl.

2. The method for high-throughput synthesis of 1-phenylazetidine compounds according to claim 1, characterized in that: The method comprises: (a) providing compounds of formula I and formula II, a base, a solvent, a transition metal, and a catalyst to each reaction chamber in a plurality of reaction chambers; (b) maintaining the plurality of reaction chambers under conditions suitable for forming compounds of formula III; (c) purifying the plurality of compounds of formula III simultaneously; and (d) evaluating one or more physical and chemical properties of the purified compounds III.

3. The method for high-throughput synthesis of 1-phenylazetidine compounds according to claim 2, characterized in that: The catalyst is selected from RuPhos, XPhos, BINAP, XantPhos, APhos, DPEphos, Brettphos, PPh3, PCy3, DPPP, CyJhonphos, DavePhos; and / or; The base is selected from DIPEA, Et3N, DBU, DBN, potassium tert-butoxide, sodium tert-butoxide, potassium phosphate, cesium carbonate, potassium carbonate, cesium fluoride, potassium acetate, potassium methoxide; and / or; The solvent is selected from Dixane, DMSO, DMF, NMP, DMAc, THF, CAN, Tol, tBuOH, t-AmOH, nBuOH, DME; and / or; The transition metal is selected from palladium acetate, Pd2(bda)3, allylpalladium chloride dimer, and Brettphos-Pd-G3.

4. The method for high-throughput synthesis of 1-phenylazetidine compounds according to claim 2, characterized in that: The multiple reaction chambers use multiple independent reaction bottles arranged in metal holes in a parallel reactor. The bottom of the parallel reactor is provided with a first rubber pad for supporting the reaction bottle, and the top is provided with a metal cover. A second rubber pad is provided between the metal cover and the reaction bottle, and a buffer film is provided between the second rubber pad and the reaction bottle.

5. The method for high-throughput synthesis of 1-phenylazetidine compounds according to claim 4, characterized in that: The method also includes using a heating stirrer to synchronously heat and stir multiple reaction bottles after the reactants are added to the reaction bottles; and after the reaction is completed, using a centrifugal rotary evaporator to synchronously rotary evaporate the multiple reaction bottles.

6. The method for high-throughput synthesis of 1-phenylazetidine compounds according to claim 5 is characterized in that a base is first added to the reaction bottle, followed by a magnetic stirrer and the compounds of formula I and formula II as substrates and a catalyst, and finally a transition metal is added; and each material is added simultaneously to all reaction bottles at one time through an auxiliary liquid storage tank.

7. The method for high-throughput synthesis of 1-phenylazetidine compounds according to claim 5 or 6, characterized in that: The heating stirrer supports the reaction bottle via a metal tray; and controls the reaction speed to be 600-700 rpm.

8. The method for high-throughput synthesis of 1-phenylazetidine compounds according to claim 3, characterized in that: The catalyst is BrettPhos, the solvent is DMF, the transition metal is Pd2(dba)3, and the base is Cs2CO3.

9. The method for high-throughput synthesis of 1-phenylazetidine compounds according to claim 2, characterized in that: The ratio of the compound represented by formula I to the compound represented by formula II, transition metal, catalyst and base is 1:(1-2):(0.005-0.01):(0.02-0.04):(3-5).

10. The method for high-throughput synthesis of 1-phenylazetidine compounds according to claim 1, characterized in that: The reaction temperature of the CN coupling reaction is 90-110°C and the reaction time is 12-24h.

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