Method for preparing benzyl ether compound by adopting micro-flow field reactor

Abstract

The invention discloses a method for preparing a benzyl ether compound by adopting a micro-flow field reactor, which comprises the following steps of: putting a homogeneous solution A containing an ethylbenzene compound, a free radical initiator, a copper catalyst, a ligand and a first solvent and a homogeneous solution B containing a benzyl alcohol compound, a reducing agent and a second solvent into a micro-flow field reaction device to react; the benzyl ether compound is obtained. According to the method, the cheap metal catalyst and the low-toxicity solvent are used, so that the synthesis cost is reduced, the reaction can be carried out at a relatively low temperature (40 DEG C), the method is green and safe, and continuous production can be realized through a micro-flow field technology. And the product yield can reach 81% at most. The method effectively overcomes the problems of complex steps, expensive catalyst requirement, low atomic efficiency and the like in the traditional synthesis route.

Description

Technical Field

[0001] The present invention relates to the field of organic chemical synthesis, and particularly to a method for preparing benzyl ether compounds by using a microfluidic reactor. Background Art

[0002] The benzyl ether structure is an important part of drugs and bioactive molecules, and appears in the structures of various drugs. The synthesis of benzyl ether is one of the common steps in the synthesis of drug molecules. Benzyl ether compounds have broad application prospects in the artificial synthesis of natural organic compounds and the construction of drug intermediates.

[0003] Traditional synthesis methods of benzyl ether compounds, such as the classic Williamson synthesis method, require the use of strong bases and halogenated hydrocarbons. The reaction conditions are relatively harsh, and side reactions such as elimination reactions are likely to occur, resulting in low yields. For some substrates with complex structures, it is also difficult to control the reaction selectivity. Moreover, the precedent of direct oxidative coupling of benzyl C-H with alcohols is limited to electron-rich compounds. For example, Lee et al. carried out site-selective alkoxylation of electron-rich benzylic C-H bonds by photoredox catalysis (Lee BJ, Deglopper KS, Yoon TP. Site-Selective Alkoxylation of Benzylic C-H Bonds by Photoredox Catalysis[J]. Angewandte Chemie (International ed. in English), 2020, 59(1): 197-202.). Transition metal-catalyzed benzyl ether synthesis, such as Ryoichi et al. effectively converted aryl benzyl carbonates into benzyl ethers by decarboxylative etherification with a palladium catalyst under neutral conditions (Kuwano R, Kusano H. Benzyl Protection of Phenols under Neutral Conditions: Palladium-Catalyzed Benzylations of Phenols[J]. Organic Letters, 2008, 10(10): 1979-1982). However, the above methods still have some disadvantages, such as the high price of palladium catalysts and defects in volatility, corrosiveness, toxicity, and carcinogenicity. Summary of the Invention

[0004] The object of the present invention is to provide a method for preparing benzyl ether compounds by copper catalysis in a microfluidic reactor, aiming at the problems of cumbersome reaction process, low reaction yield, and difficulty in large-scale synthesis existing in the existing synthesis technology of benzyl ether compounds.

[0005] In order to achieve the above object, the technical solution provided by the present invention is as follows:

[0006] A method for preparing benzyl ether compounds by using a microfluidic reaction device, comprising reacting a homogeneous solution A containing an ethylbenzene compound, a radical initiator, a copper catalyst, a ligand and a first solvent with a homogeneous solution B containing a benzyl alcohol compound, a reducing agent and a second solvent in the microfluidic reaction device to obtain the benzyl ether compound;

[0007] The structural formula of the ethylbenzene compound is as shown in Formula I; the structural formula of the benzyl alcohol compound is as shown in Formula II; the structural formula of the benzyl ether compound is as shown in Formula III;

[0008]

[0009] Wherein,

[0010] R 1 is selected from any one of hydrogen, aryl and methoxy;

[0011] R 2 is selected from any one of hydrogen, halogen, aryl, methoxy and nitro.

[0012] Wherein, the ethylbenzene compound is preferably any one of ethylbenzene, 4-ethylbiphenyl and 4-ethylanisole.

[0013] Wherein, the benzyl alcohol compound is preferably any one of benzyl alcohol, 4-chlorobenzyl alcohol, 4-methoxybenzyl alcohol, 2-bromobenzyl alcohol, 3-bromobenzyl alcohol and p-nitrobenzyl alcohol.

[0014] Wherein, the radical initiator is any one or a combination of several of N-fluorobis(phenylsulfonamide) (NFSI), tert-butyl peroxybenzoate, benzoyl peroxide, potassium persulfate, iodobenzene diacetate, iodobenzene bis(trifluoroacetate) and selective fluorinating reagents, and is preferably N-fluorobis(phenylsulfonamide) (NFSI).

[0015] Wherein, the copper catalyst is any one or a combination of several of cuprous chloride, cuprous bromide, copper chloride and copper(II) tetra(acetonitrile) tetrafluoroborate; preferably cuprous chloride and / or cuprous bromide; more preferably cuprous chloride.

[0016] Among them, the ligand is any one or a combination of several of 2,2'-dipyridine, 4,4'-di-tert-butyl-2,2'-dipyridine, 4,4'-bis(trifluoromethyl)-2,2'-dipyridine, 2,9-dimethyl-1,10-phenanthroline, 4,7-dichloro-1,10-phenanthroline, 4,7-dimethoxy-1,10-phenanthroline, 2,2-bis(2-oxazoline) (Biox), 2-ethyl-4,4-dimethyl-2-oxazoline, N-methylimidazole and pyridine. It is preferably 2,2-bis(2-oxazoline) or 2-ethyl-4,4-dimethyl-2-oxazoline, and further preferably 2,2-bis(2-oxazoline).

[0017] Among them, the reducing agent is any one or a combination of several of dimethyl phosphite, diethyl phosphite, diisopropyl phosphite, di-tert-butyl phosphite, di-n-butyl phosphite, methyldimethoxysilane, methyldiethoxysilane, diethyl 1,2-hydrazinedicarboxylate, tributylphosphine and sodium ascorbate. It is preferably any one or a combination of several of dimethyl phosphite, diethyl phosphite, diisopropyl phosphite, dibutyl phosphite and methyldimethoxysilane, and further preferably dimethyl phosphite.

[0018] Among them, the first solvent is any one or a combination of several of dichloromethane (DCM), 1,2-dichloroethane, dimethyl carbonate, ethyl acetate, benzene, methanol, hexafluoroisopropanol (HFIP). It is preferably any one or a combination of several of dichloromethane, 1,2-dichloroethane, methanol and hexafluoroisopropanol, and further preferably a combination of dichloromethane and hexafluoroisopropanol; preferably, when the first solvent is a combination of dichloromethane and hexafluoroisopropanol, the volume ratio of dichloromethane to hexafluoroisopropanol is 2-6:1; most preferably, when the first solvent is a combination of dichloromethane and hexafluoroisopropanol, the volume of dichloromethane to hexafluoroisopropanol is 4:1.

[0019] Among them, the second solvent is any one or a combination of several of dichloromethane (DCM), 1,2-dichloroethane, dimethyl carbonate, ethyl acetate, benzene, methanol, hexafluoroisopropanol (HFIP). It is preferably any one or a combination of several of dichloromethane, 1,2-dichloroethane, methanol and hexafluoroisopropanol, and further preferably a combination of dichloromethane and hexafluoroisopropanol; preferably, when the first solvent is a combination of dichloromethane and hexafluoroisopropanol, the volume ratio of dichloromethane to hexafluoroisopropanol is 2-6:1; most preferably, when the first solvent is a combination of dichloromethane and hexafluoroisopropanol, the volume of dichloromethane to hexafluoroisopropanol is 4:1.

[0020] Among them, in the mixed solution formed by mixing the homogeneous solution A and the homogeneous solution B, the initial concentration of the ethylbenzene compound is 0.1 to 0.4 mmol / mL, preferably 0.1 to 0.3 mmol / mL, and more preferably 0.1 to 0.2 mmol / mL;

[0021] Among them, in the mixed solution formed by mixing the homogeneous solution A and the homogeneous solution B, the initial molar ratio of the benzyl alcohol compound to the ethylbenzene compound is (1.0 to 5.0):1, preferably (3.0 to 5.0):1, and more preferably 5:1.

[0022] Among them, in the mixed solution formed by mixing the homogeneous solution A and the homogeneous solution B, the initial molar ratio of the radical initiator to the ethylbenzene compound is (0.5 to 2.5):1, preferably (1 to 2):1, and more preferably 2:1.

[0023] Among them, in the mixed solution formed by mixing the homogeneous solution A and the homogeneous solution B, the initial molar ratio of the copper catalyst to the ethylbenzene compound is (0.05 to 0.3):1, preferably (0.05 to 0.2):1, and more preferably 0.1:1.

[0024] Among them, in the mixed solution formed by mixing the homogeneous solution A and the homogeneous solution B, the initial molar ratio of the ligand to the ethylbenzene compound is (0.05 to 0.3):1, preferably (0.05 to 0.2):1, and more preferably 0.1:1.

[0025] Among them, in the mixed solution formed by mixing the homogeneous solution A and the homogeneous solution B, the initial molar ratio of the reducing agent to the ethylbenzene compound is (0.25 to 1):1, preferably (0.5 to 1):1, and more preferably 0.5:1.

[0026] Among them, the flow rates of the homogeneous solution A and the homogeneous solution B pumped into the microfluidic reaction device are both 0.02 to 0.05 mL / min, preferably 0.025 mL / min.

[0027] Among them, the reaction temperature of the reaction is 20 to 80 °C, preferably 40 °C; the residence time of the reaction is 10 to 30 min, preferably 20 min.

[0028] Among them, the microfluidic reaction device includes two syringe pumps, a Y-shaped micromixer, a microfluidic reactor and a product receiver. The two syringe pumps are connected in parallel to the Y-shaped micromixer through connecting pipes, and the Y-shaped micromixer, the microfluidic reactor and the product receiver are connected in series through connecting pipes in sequence; the microfluidic reaction device is as Figure 1 andFigure 2 as shown

[0029] Among them, the microfluidic reactor is a pore structure, and the material is perfluoroalkoxy alkane;

[0030] The inner diameter of the pores of the microfluidic reactor is 0.5 - 2.0 mm, preferably 0.5 - 1.0 mm, and more preferably 0.6 mm;

[0031] The pore volume of the microfluidic reactor is 0.3 - 5.0 mL, preferably 0.3 - 2.0 mL, and more preferably 1.0 mL.

[0032] Preferably, the specific method for preparing benzyl ether compounds by the method of the present invention through a microfluidic reaction device is: transferring the homogeneous solution A and the homogeneous solution B to two syringe pumps of the microfluidic reaction device respectively, pumping the homogeneous solution A and the homogeneous solution B into the connecting pipeline through the syringe pumps, gradually mixing evenly after passing through the Y-shaped micromixer, and entering the microfluidic reactor for reaction.

[0033] Beneficial effects:

[0034] Compared with the prior art, the present invention has the following advantages:

[0035] (1) In the preparation method provided by the present invention, the reagents used have low pollution, high safety, simple experimental operation, mild reaction conditions, are conducive to large-scale continuous production, and effectively overcome the problems existing in the traditional synthesis route, such as complex steps, long reaction time, the need for expensive catalysts, and low atom utilization rate.

[0036] (2) Compared with the traditional synthesis method and the palladium-catalyzed synthesis method, the present invention synthesizes benzyl ether by copper catalysis in a microfluidic reactor, without the need to add expensive palladium catalysts, reduces production costs, and has milder reaction conditions, can effectively avoid strong exothermic processes, and greatly improves reaction safety.

[0037] (3) The yield of benzyl ether compounds prepared by the preparation method of the present invention can reach 55 - 81%. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] The following further specifically describes the present invention in conjunction with the drawings and specific embodiments, and the above and / or other advantages of the present invention will become clearer.

[0039] Figure 1 is a schematic diagram of the reaction process of the present invention;

[0040] Figure 2 is a physical diagram of the microfluidic reaction device of the present invention;

[0041] Figure 31H NMR spectrum of product 3aa in Example 1;

[0042] Figure 4 13C NMR spectrum of product 3aa in Example 1. Detailed implementation manners

[0043] The present invention will be further described according to the following embodiments. It should be understood that the following implementation manners are only used to illustrate the present invention, rather than limiting the present invention.

[0044] Unless otherwise specified, the reactions described in the following embodiments are carried out at 40 °C.

[0045] In the following embodiments, "mol%" in the usage amount of chemical substances represents the percentage of the molar ratio of the chemical substance to the ethylbenzene compound. For example, 10 mol% of cuprous chloride in Example 1 represents that the percentage of the molar ratio of cuprous chloride to the ethylbenzene compound 4-ethylbiphenyl in Example 1 is 10%.

[0046] The reaction flow schematic diagram of the present invention is as Figure 1 shown.

[0047] The microfluidic reaction device used in the embodiments of the present invention is as Figure 2 shown, and includes two injection pumps, a Y-shaped micro mixer, a microfluidic reactor and a product receiver. Among them, the two injection pumps are connected in parallel to the Y-shaped micro mixer through connecting pipes, and the Y-shaped micro mixer, the microfluidic reactor and the product receiver are connected in series through connecting pipes in sequence. Among them, the microfluidic reactor is a pore structure, and the material is perfluoroalkoxy alkane. The inner diameter of the pipeline of the microfluidic reactor is 0.5-2.0 mm, and the inner diameter of the pipeline of the microfluidic reactor in the embodiments of the present invention is 1.0 mm.

[0048] Example 1

[0049]

[0050] Weigh successively 4-ethylbiphenyl (36.45 mg, 0.2 mmol, 1.0 equiv.), N-fluorobenzenesulfonimide (126.14 mg, 0.4 mmol, 2.0 equiv.), copper(I) chloride (1.98 mg, 0.02 mmol, 10 mol%), 2,2-bis(2-oxazoline) (2.80 mg, 0.02 mmol, 10 mol%) and add to the solvent (DCM:HFIP = 4:1, 0.5 mL), and stir well to dissolve it to obtain homogeneous solution A; weigh successively benzyl alcohol (103.5 μL, 1.0 mmol, 5.0 equiv.), dimethyl phosphite (9.2 μL, 0.1 mmol, 0.5 equiv.), and add to the solvent (DCM:HFIP = 4:1, 0.5 mL), and stir well to dissolve it to obtain homogeneous solution B. Transfer homogeneous solution A and homogeneous solution B to syringes respectively, and use an infusion pump to introduce them into a heatable microfluidic reactor, with the pumping flow rate of both being 0.025 mL / min, and monitor the reaction process by thin layer chromatography (TLC), with a residence time of 20 minutes. After the reaction is completed, quench the reaction, extract the reaction solution with dichloromethane and saturated brine (3 × 10 mL), combine the organic layers, dry with anhydrous sodium sulfate, distill off the solvent under reduced pressure, and separate by silica gel column chromatography (eluent: petroleum ether:ethyl acetate) to obtain 43.22 mg of product 3aa, with a yield of 75%. The characterization data of product 3aa are as follows (as Figure 3 and Figure 4 shown): 1 H NMR (400 MHz, CDCl3) δ 7.72–7.54 (m, 6H), 7.53–7.43 (m, 2H), 7.41–7.27 (m, 6H), 4.65–4.54 (m, 1H), 4.53–4.33 (m, 2H), 1.55 (d, J = 6.5 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 142.8, 141.0, 140.5, 138.7, 128.8, 128.4, 127.8, 127.6, 127.3, 126.8, 72.2, 70.4, 24.3. HRMS (ESI) m / z: calcd for C 21 H 20 ONa [M+Na] + : 311.1406, found: 311.1393.

[0051] Example 2

[0052]

[0053] Weigh successively 4-ethylbiphenyl (36.45 mg, 0.2 mmol, 1.0 equiv.), N-fluorobenzenesulfonimide (126.14 mg, 0.4 mmol, 2.0 equiv.), copper(I) chloride (1.98 mg, 0.02 mmol, 10 mol%), 2,2-bis(2-oxazoline) (2.80 mg, 0.02 mmol, 10 mol%), add the solvent (DCM:HFIP = 4:1, 0.5 mL) and stir well to dissolve it to obtain a homogeneous solution A; 4-chlorobenzyl alcohol (142.58 mg, 1.0 mmol, 5.0 equiv.), dimethyl phosphite (9.2 μL, 0.1 mmol, 0.5 equiv.), add the solvent (DCM:HFIP = 4:1, 0.5 mL) and stir well to dissolve it to obtain a homogeneous solution B. Transfer the homogeneous solution A and the homogeneous solution B into syringes respectively, and use an injection pump to introduce them into a heatable microfluidic reactor at a pumping rate of 0.025 mL / min, and monitor the reaction process by TLC with a residence time of 20 minutes. After the reaction is completed, quench the reaction. The reaction solution is extracted with dichloromethane and saturated brine (3×10 mL), the organic layers are combined, dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. Then, the product 3ab (48.96 mg) is obtained by silica gel column chromatography (eluent: petroleum ether:ethyl acetate) with a yield of 76%. The characterization data of the product 3ab are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.72–7.60 (m, 4H), 7.60–7.36 (m, 5H), 7.36–7.26 (m, 4H), 5.01–4.59 (m, 1H), 4.39–4.22 (m, 2H), 1.53 (d, J = 6.7 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 143.0, 140.1, 138.8, 134.0, 133.8, 128.9, 128.8, 128.6, 127.7, 127.0, 125.6, 78.3, 71.0, 23.0. HRMS (ESI) m / z: calcd for C 21 H 20 OCl [M + H] + : 323.1197, found: 323.1211.

[0054] Example 3

[0055]

[0056] Weigh sequentially 4-ethylbiphenyl (36.45 mg, 0.2 mmol, 1.0 equiv.), N-fluorobenzenesulfonimide (126.14 mg, 0.4 mmol, 2.0 equiv.), copper(I) chloride (1.98 mg, 0.02 mmol, 10

[0057] mol%), 2,2-bis(2-oxazoline) (2.80 mg, 0.02 mmol, 10 mol%), add the solvent (DCM:HFIP = 4:1, 0.5 mL) and stir well to dissolve it to obtain a homogeneous solution A; 4-methoxybenzyl alcohol (138.16 mg, 1.0 mmol, 5.0 equiv.), dimethyl phosphite (9.2 μL, 0.1 mmol, 0.5 equiv.), add the solvent (DCM:HFIP = 4:1, 0.5 mL) and stir well to dissolve it to obtain a homogeneous solution B. Transfer the homogeneous solution A and the homogeneous solution B to syringes respectively, and use an injection pump to introduce them into a heatable microfluidic reactor. The pumping rate is 0.025 mL / min, and TLC is used to monitor the reaction progress. The residence time is 20 minutes. After the reaction is completed, quench the reaction. The reaction solution is extracted with dichloromethane and saturated brine (3×10 mL), the organic layers are combined, dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. Then, the product 3ac (47.09 mg) is obtained by silica gel column chromatography (the eluent is petroleum ether:ethyl acetate), and the yield is 74%. The characterization data of the product 3ab are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.72–7.59 (m, 4H), 7.60–7.34 (m, 5H), 7.34–6.87 (m, 4H), 4.82 (m, 1H), 4.54–4.03 (m, 2H), 3.80 (s, 3H), 1.55 (d, J = 6.7 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 159.2, 143.0, 140.1, 138.8, 131.6, 129.36, 128.9, 127.7, 127.0, 125.6, 113.8, 78.3, 71.0, 55.4, 23.0. HRMS (ESI) m / z: calcd for C 22 H 23 O2 [M+H] + : 319.1693, found: 319.1705.

[0058] Example 4

[0059]

[0060] Weigh successively 4-ethylbiphenyl (36.45 mg, 0.2 mmol, 1.0 equiv.), N-fluorobenzenesulfonimide (126.14 mg, 0.4 mmol, 2.0 equiv.), copper(I) chloride (1.98 mg, 0.02 mmol, 10 mol%), 2,2-bis(2-oxazoline) (2.80 mg, 0.02 mmol, 10 mol%), add the solvent (DCM:HFIP = 4:1, 0.5 mL) and stir well to dissolve it to obtain homogeneous solution A; 4-nitrobenzyl alcohol (153.14 mg, 1.0 mmol, 5.0 equiv.), dimethyl phosphite (9.2 μL, 0.1 mmol, 0.5 equiv.), add the solvent (DCM:HFIP = 4:1, 0.5 mL) and stir well to dissolve it to obtain homogeneous solution B. Transfer homogeneous solution A and homogeneous solution B to syringes respectively, and use an injection pump to introduce them into a heatable microfluidic reactor. The pumping rate is 0.025 mL / min, and monitor the reaction process by TLC. The residence time is 20 minutes. After the reaction is completed, quench the reaction. The reaction solution is extracted with dichloromethane and saturated brine (3×10 mL), the organic layers are combined, dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. Then, the product 3ad (53.97 mg) is obtained by silica gel column chromatography (the eluent is petroleum ether:ethyl acetate), and the yield is 81%. The characterization data of the product 3ad are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.25–8.10 (m, 2H), 7.73–7.60 (m, 4H), 7.60–7.57 (m, 2H), 7.56 (d, J = 7.3 Hz, 2H), 7.44 (t, J = 7.5 Hz, 2H), 7.33 (m, 1H), 5.04–4.70 (m, 1H), 4.55–4.16 (m, 2H), 1.53 (d, J = 6.9 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 147.6, 143.0, 140.1, 138.8, 138.5, 128.9, 128.4, 127.7, 127.0, 125.6, 123.8, 78.3, 71.0, 23.1. HRMS (ESI) m / z: calcd for C 21 H 19 O3NNa [M+Na] + : 356.1527, found: 356.1536.

[0061] Example 5

[0062]

[0063] Weigh successively 4-ethylbiphenyl (36.45 mg, 0.2 mmol, 1.0 equiv.), N-fluorobenzenesulfonimide (126.14 mg, 0.4 mmol, 2.0 equiv.), copper(I) chloride (1.98 mg, 0.02 mmol, 10 mol%), 2,2'-bis(2-oxazoline) (2.80 mg, 0.02 mmol, 10 mol%), add solvent (DCM:HFIP = 4:1, 0.5 mL) and stir well to dissolve it to obtain homogeneous solution A; 3-bromobenzyl alcohol (119.9 μL, 1.0 mmol, 5.0 equiv.), dimethyl phosphite (9.2 μL, 0.1 mmol, 0.5 equiv.), add solvent (DCM:HFIP = 4:1, 0.5 mL) and stir well to dissolve it to obtain homogeneous solution B. Transfer homogeneous solution A and homogeneous solution B into syringes respectively, and use an infusion pump to introduce them into a heatable microfluidic reactor. The pumping rate is 0.025 mL / min, and monitor the reaction process by TLC. The residence time is 20 minutes. After the reaction is completed, quench the reaction. The reaction solution is extracted with dichloromethane and saturated brine (3 × 10 mL), the organic layers are combined, dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. Then, product 3ae (57.10 mg) is obtained by silica gel column chromatography (eluent: petroleum ether:ethyl acetate), and the yield is 78%. The characterization data of product 3ae are as follows: 1 H NMR(400MHz,CDCl3)δ7.72–7.60(m,4H),7.59(m,2H),7.55(m,1H),7.51(m,1H),7.44(t,J=7.5Hz,2H),7.33(m,2H),7.23(t,J=7.4Hz,1H),5.11–4.70(m,1H),4.64–4.01(m,2H),1.53(d,J=6.9Hz,3H). 13 C NMR(100MHz,CDCl3)δ143.0,140.1,138.8,138.8,130.6,130.4,129.9,128.9,127.7,127.0,125.6,125.2,122.4,78.3,71.7,23.1.HRMS(ESI)m / z:calcd for C 21 H 19 OBrNa[M+Na] + :389.0511,found:389.0523.

[0064] Example 6

[0065]

[0066] Weigh successively 4-ethylbiphenyl (36.45 mg, 0.2 mmol, 1.0 equiv.), N-fluorobenzenesulfonimide (126.14 mg, 0.4 mmol, 2.0 equiv.), copper(I) chloride (1.98 mg, 0.02 mmol, 10 mol%), 2,2-bis(2-oxazoline) (2.80 mg, 0.02 mmol, 10 mol%), add solvent (DCM:HFIP = 4:1, 0.5 mL) and stir well to dissolve to obtain homogeneous solution A; 2-bromobenzyl alcohol (187.03 mg, 1.0 mmol, 5.0 equiv.), dimethyl phosphite (9.2 μL, 0.1 mmol, 0.5 equiv.), add solvent (DCM:HFIP = 4:1, 0.5 mL) and stir well to dissolve to obtain homogeneous solution B. Transfer homogeneous solution A and homogeneous solution B into syringes respectively, and use an infusion pump to introduce them into a heatable microfluidic reactor. The pumping rate is 0.025 mL / min, and monitor the reaction process by TLC. The residence time is 20 minutes. After the reaction is completed, quench the reaction. The reaction solution is extracted with dichloromethane and saturated brine (3×10 mL). Combine the organic layers, dry with anhydrous sodium sulfate, remove the solvent by rotary evaporation, and obtain 51.98 mg of product 3af by silica gel column chromatography (eluent: petroleum ether:ethyl acetate), with a yield of 71%. The characterization data of product 3af are as follows: 1 H NMR(400MHz,CDCl3)δ7.71–7.61(m,4H),7.58(m,3H),7.44(t,J=7.5Hz,2H),7.38–7.25(m,3H),7.08m,1H),4.86–4.79(m,1H),4.79–4.14(m,2H),1.53(d,J=6.7Hz,3H). 13 C NMR(100MHz,CDCl3)δ143.0,140.1,138.8,135.8,131.8,129.2,128.9,128.7,127.8,127.7,127.0,126.4,125.6,78.3,70.6,23.0.HRMS(ESI)m / z:calcd for C 21 H 20 OBr[M+H] + :367.0692,found:367.0706.

[0067] Example 7

[0068]

[0069] Weigh successively N-fluorobenzenesulfonimide (126.14 mg, 0.4 mmol, 2.0 equiv.), copper(I) chloride (1.98 mg, 0.02 mmol, 10 mol%), 2,2-bis(2-oxazoline) (2.80 mg, 0.02 mmol, 10 mol%), ethylbenzene (24.5 μL, 0.2 mmol, 1.0 equiv.), add solvent (DCM:HFIP = 4:1, 0.5 mL) and stir well to dissolve it to obtain homogeneous solution A; benzyl alcohol (103.5 μL, 1.0 mmol, 5.0 equiv.), dimethyl phosphite (9.2 μL, 0.1 mmol, 0.5 equiv.), add solvent (DCM:HFIP = 4:1, 0.5 mL) and stir well to dissolve it to obtain homogeneous solution B. Transfer homogeneous solution A and homogeneous solution B into syringes respectively, and use an injection pump to introduce them into a heatable microfluidic reactor. The pumping rate is 0.025 mL / min, and TLC is used to monitor the reaction progress with a residence time of 20 minutes. After the reaction is completed, quench the reaction. The reaction solution is extracted with dichloromethane and saturated brine (3×10 mL). Combine the organic layers, dry with anhydrous sodium sulfate, remove the solvent by rotary evaporation, and then obtain 31.39 mg of product 3ba by silica gel column chromatography (eluent: petroleum ether:ethyl acetate) with a yield of 74%. The characterization data of product 3ba are as follows: 1 H NMR(400MHz,CDCl3)δ7.59–7.34(m,4H),7.31(s,6H),5.11–4.69(m,1H),4.36(m,2H),1.49(d,J=6.9Hz,3H). 13 C NMR(100MHz,CDCl3)δ143.5,137.9,128.5,128.0,128.0,127.7,127.5,127.0,78.3,71.0,23.1.HRMS(ESI)m / z:calcd for C 15 H 16 ONa[M+Na] + :235.1093,found:235.1107.

[0070] Example 8

[0071]

[0072] Weigh successively N-fluorobenzenesulfonimide (126.14 mg, 0.4 mmol, 2.0 equiv.), copper(I) chloride (1.98 mg, 0.02 mmol, 10 mol%), 2,2-bis(2-oxazoline) (2.80 mg, 0.02 mmol, 10 mol%), 4-ethylanisole (28.4 μL, 0.2 mmol, 1.0 equiv.), add the solvent (DCM:HFIP = 4:1, 0.5 mL) and stir well to dissolve it to obtain homogeneous solution A; benzyl alcohol (103.5 μL, 1.0 mmol, 5.0 equiv.), dimethyl phosphite (9.2 μL, 0.1 mmol, 0.5 equiv.), add the solvent (DCM:HFIP = 4:1, 0.5 mL) and stir well to dissolve it to obtain homogeneous solution B. Transfer homogeneous solution A and homogeneous solution B to syringes respectively, and use an infusion pump to introduce them into a heatable microfluidic reactor. The pumping rate is 0.025 mL / min, and TLC is used to monitor the reaction progress. The residence time is 20 minutes. After the reaction is completed, quench the reaction. The reaction solution is extracted with dichloromethane and saturated brine (3×10 mL). Combine the organic layers, dry with anhydrous sodium sulfate, distill off the solvent under reduced pressure, and obtain 34.86 mg of product 3ca by silica gel column chromatography (eluent: petroleum ether:ethyl acetate), with a yield of 72%. The characterization data of product 3ca are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.39–7.32(m,2H),7.31(s,5H),6.97–6.81(m,2H),4.93–4.64(m,1H),4.29(m,2H),3.80(s,3H),1.52(d,J=6.8Hz,3H). 13 CNMR(100MHz,CDCl3)δ158.9,139.3,137.9,128.5,128.0,127.7,127.3,113.7,78.3,71.0,55.4,23,0.HRMS(ESI)m / z:calcd for C 16 H 18 O2Na[M+Na] + :265.1199,found:265.1205.

[0073] Comparative Example 9

[0074]

[0075] Weigh successively 4-ethylbiphenyl (36.45 mg, 0.2 mmol, 1.0 equiv.), N-fluorobenzenesulfonimide (126.14 mg, 0.4 mmol, 2.0 equiv.), copper(I) chloride (1.98 mg, 0.02 mmol, 10 mol%), 2,2-bis(2-oxazoline) (2.80 mg, 0.02 mmol, 10 mol%), benzyl alcohol (103.5 μL, 1.0 mmol, 5.0 equiv.), dimethyl phosphite (9.2 μL, 0.1 mmol, 0.5 equiv.), add the solvent (DCM:HFIP = 4:1, 1.0 mL) and stir well to dissolve. Add this reaction solution to a test tube and react at 40 °C for 16 h. After the reaction is completed, quench the reaction. Extract the reaction solution with dichloromethane and saturated brine (3 × 10 mL). Combine the organic layers, dry over anhydrous sodium sulfate, remove the solvent by distillation under reduced pressure, and obtain 31.69 mg of product 3aa by silica gel column chromatography (the eluent is petroleum ether:ethyl acetate), with a yield of 55%. The characterization data of product 3aa are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.72–7.53 (m, 4H), 7.53–7.38 (m, 5H), 7.38–7.27 (m, 5H), 5.02–4.58 (m, 1H), 4.57–4.33 (m, 2H), 1.55 (d, J = 6.5 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 142.9, 141.1, 140.6, 138.7, 128.9, 128.5, 127.9, 127.4, 127.2, 126.9, 72.2, 70.5, 24.3. HRMS (ESI) m / z: calcd for C 21 18 21 H + 10

[0076] Examples 1–8 are methods for preparing benzyl ether compounds using a microfluidic reactor, and Comparative Example 9 is a method for preparing benzyl ether compounds using a conventional method. By comparing the yields of benzyl ether compounds in Examples 1–8 and Comparative Example 9, it can be seen that the use of a microfluidic reaction device to prepare benzyl ether compounds in the present invention can significantly improve the yield of benzyl ether compounds (see Table 1 in detail. In Table 1, 1a in the raw materials is 4-ethylbiphenyl, 1b is ethylbenzene, 1c is 4-ethylanisole, 2a is benzyl alcohol, 2b is 4-chlorobenzyl alcohol, 2c is 4-methoxybenzyl alcohol, 2d is 4-nitrobenzyl alcohol, 2e is 3-bromobenzyl alcohol, and 2f is 2-bromobenzyl alcohol).

[0077] Table 1 Main parameters and yields of Examples 1–8 and Comparative Example 9

[0078]

[0079] Example 10

[0080] In this example, optimization experiments were respectively carried out on the types of copper catalyst, radical initiator, ligand, reducing agent and solvent. During the experiment, the experimental method and the ratios of raw material 2 (benzyl alcohol compounds), copper catalyst, radical initiator, ligand, reducing agent and solvent to raw material 1 (ethylbenzene compounds) were the same as those in Example 1. The experimental results are shown in Tables 2 to 6 respectively.

[0081] Table 2 Optimization experiment on the type of copper catalyst

[0082]

[0083] Table 3 Optimization experiment on the type of radical initiator

[0084]

[0085] Table 4 Optimization experiment on the type of ligand

[0086]

[0087] Table 5 Optimization experiment on the type of reducing agent

[0088]

[0089] Table 6 Optimization experiment on the type of solvent

[0090]

[0091] Example 11

[0092] In this example, optimization experiments were respectively carried out on the addition amounts of copper catalyst, radical initiator, ligand, reducing agent and solvent. During the experiment, the experimental method was the same as that in Example 1. Except for the addition amounts of the reagents listed in the table, for the other reagents whose addition amounts were not listed in the table, their ratios to raw material 1 (ethylbenzene compounds) were the same as those in Example 1. The experimental results are shown in Tables 7 to 11 respectively.

[0093] Table 7 Optimization experiment on the addition amount of copper catalyst

[0094]

[0095] Table 8 Optimization experiment on the addition amount of radical initiator

[0096]

[0097] Table 9 Optimization experiment on the addition amount of ligand

[0098]

[0099] Table 10 Optimization Experiment on Reducing Agent Dosage

[0100]

[0101]

[0102] Table 11 Optimization Experiment on Solvent Dosage

[0103]

[0104] The present invention provides an idea and method for preparing benzyl ether compounds by using a microfluidic reaction device. There are many methods and ways to specifically implement this technical solution. The above is only the preferred embodiment of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention. Each component not clearly defined in this embodiment can be realized by the prior art.

Claims

1. A method for preparing benzyl ether compounds using a microfluidic reaction device, characterized in that, A homogeneous solution A containing an ethylbenzene compound, a radical initiator, a copper catalyst, a ligand, and a first solvent is reacted with a homogeneous solution B containing a benzyl alcohol compound, a reducing agent, and a second solvent in a microfluidic reaction device to obtain the benzyl ether compound; The structural formula of the ethylbenzene compound is shown in Formula I; the structural formula of the benzyl alcohol compound is shown in Formula II; The structural formula of the benzyl ether compound is shown in Formula III; Wherein, R 1 selected from any one of hydrogen, aryl, and methoxy; R 2 Selected from any one of hydrogen, halogen, aryl, methoxy and nitro.

2. The method according to claim 1, wherein The ethylbenzene compound is preferably any one of ethylbenzene, 4-ethylbiphenyl, and 4-ethylanisole; the benzyl alcohol compound is preferably any one of benzyl alcohol, 4-chlorobenzyl alcohol, 4-methoxybenzyl alcohol, 2-bromobenzyl alcohol, 3-bromobenzyl alcohol, and p-nitrobenzyl alcohol.

3. The method according to claim 1, wherein The radical initiator is any one or a combination of several of N-fluorodibenzenesulfonamide, tert-butyl peroxybenzoate, benzoyl peroxide, potassium persulfate, iodobenzene diacetate, iodobenzene bis(trifluoroacetate), and a selective fluorine reagent.

4. The method according to claim 1, wherein The copper catalyst is any one or a combination of several of cuprous chloride, cuprous bromide, copper chloride, and tetrakis(acetonitrile)copper tetrafluoroborate.

5. The method according to claim 1, wherein The ligand is any one or a combination of several of 2,2'-dipyridine, 4,4'-di-tert-butyl-2,2'-dipyridine, 4,4'-bis(trifluoromethyl)-2,2'-dipyridine, 2,9-dimethyl-1,10-phenanthroline, 4,7-dichloro-1,10-phenanthroline, 4,7-dimethoxy-1,10-phenanthroline, 2,2-bis(2-oxazoline), 2-ethyl-4,4-dimethyl-2-oxazoline, N-methylimidazole, and pyridine.

6. The method according to claim 1, wherein The reducing agent is any one or a combination of several of dimethyl phosphite, diethyl phosphite, diisopropyl phosphite, di-tert-butyl phosphite, dibutyl phosphite, methyldimethoxysilane, methyldiethoxysilane, diethyl 1,2-hydrazinedicarboxylate, tributylphosphine, and sodium ascorbate.

7. The method according to claim 1, characterized in that The first solvent is any one or a combination of several of dichloromethane, 1,2-dichloroethane, dimethyl carbonate, ethyl acetate, benzene, methanol, and hexafluoroisopropanol; the second solvent is any one or a combination of several of dichloromethane, 1,2-dichloroethane, dimethyl carbonate, ethyl acetate, benzene, methanol, and hexafluoroisopropanol.

8. The method according to claim 1, characterized in that, In the mixed solution formed by mixing the homogeneous solution A and the homogeneous solution B, the initial concentration of the ethylbenzene compound is 0.1 - 0.4 mmol / mL, the initial molar ratio of the benzyl alcohol compound to the ethylbenzene compound is (1.0 - 5.0):1, the initial molar ratio of the radical initiator to the ethylbenzene compound is (0.5 - 2.5):1, the initial molar ratio of the copper catalyst to the ethylbenzene compound is (0.05 - 0.25):1, the initial molar ratio of the ligand to the ethylbenzene compound is (0.05 - 0.25):1, and the initial molar ratio of the reducing agent to the ethylbenzene compound is (0.25 - 1):

1.

9. The method according to claim 1, wherein The flow rates of the homogeneous solution A and the homogeneous solution B pumped into the microfluidic reaction device are both 0.02 - 0.05 mL / min.

10. The method according to claim 1, wherein The reaction temperature of the said reaction is 20 to 80 °C, and the reaction residence time is 10 min to 30 min.

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