A method for synthesizing dihydrofuran containing 1,3-indanedione spiro ring skeleton using a microchannel reaction device

Abstract

The invention discloses a method for synthesizing a dihydrofuran compound containing a 1,3-indenedione spiro ring skeleton as shown in III using a microchannel reaction device, using 2-benzylidene-1,3-indenedione compound I and ethyl benzoyl acetate compound II as reaction raw materials, and preparing by continuous reaction using a microchannel reaction device, wherein the microchannel reaction device includes a feed pump, a micro mixer and a microreactor connected in sequence by a pipeline. Compared with the prior art, the present invention uses 2-benzylidene-1,3-indenedione compound as a substrate to prepare a new dihydrofuran containing a 1,3-indenedione spiro ring skeleton for the first time, and the method avoids multi-component reaction, uses a non-metallic catalyst and a low-toxic solvent, and quickly and efficiently produces a green and environmentally friendly synthetic product. #imgabs0#Wherein, R1 is selected from halogenated benzene, C1-C4 alkylbenzene, C1-C4 alkoxybenzene, nitrobenzene, furan or naphthalene; R2 is selected from halogenated benzene, C1-C4 alkylbenzene, C1-C4 alkoxybenzene, nitrobenzene, furan, thiophene, pyridyl or naphthalene.

Description

Technical Field

[0001] The invention belongs to the technical field of dihydrofuran synthesis, and particularly relates to a method for synthesizing dihydrofuran containing a spirocyclic 1,3-indanedione structure by utilizing a microchannel reaction device. Background Art

[0002] The 2,3-dihydrofuran skeleton is an important class of heterocyclic compounds, which is commonly found in a variety of natural products with biological activity. In addition, it is also an important class of synthetic intermediates. Many compounds containing this structural unit have a wide range of pharmaceutical activities, including antibacterial, anti-inflammatory, anti-cardiovascular and cerebrovascular disease, anti-cancer, anti-Parkinson's disease, etc. Therefore, researchers have conducted long-term research on the methods of synthesizing such compounds.

[0003] At present, the preparation methods of dihydrofuran mainly include: (1) a series of dihydrofuran derivatives are synthesized by two-step reaction of 1,3-dicarbonyl compounds with unsaturated carbonyl compounds under the catalysis of iodine, which can be referred to in the literature (Tetrahedron Letters., 2017, 58, 541-545); (2) a series of multi-functional substituted 2,3-dihydrofuran derivatives are prepared by a multi-component one-pot method using nitroolefins, aldehydes and 1,3-dicarbonyl compounds with the Lewis base proline as catalyst, which can be referred to in the literature (Org Lett. 2010, 12, 2064-2067); (3) a series of multi-substituted dihydrofuran derivatives are obtained by intermolecular cyclization reaction of 1,3-dicarbonyl compounds with aromatic olefins under the catalysis of Cu(I) / Cu(II), which can be referred to in the literature (Chemistry-A European Journal, 2016, 47, 18925-18929). Although there are many routes for preparing 2,3-dihydrofuran, these methods still have some obvious defects: the use of transition metal catalysis, multi-step reaction, multi-component reaction, complex reaction conditions, long reaction time, low atom utilization, environmental unfriendliness, etc., which greatly limit their industrial application. Summary of the invention

[0004] Purpose of the invention: In view of the shortcomings of the prior art, the present invention provides a method for synthesizing dihydrofuran containing a 1,3-indanedione spiro ring skeleton using a microchannel reaction device to solve the problems of complicated reaction steps, long reaction time, low reaction efficiency, etc. in the prior art. Without using a metal catalyst, the synthesis of dihydrofuran containing a 1,3-indanedione spiro ring skeleton is achieved simply and efficiently.

[0005] Technical solution: In order to solve the above technical problems, the present invention discloses a method for synthesizing a dihydrofuran compound containing a 1,3-indanedione spirocyclic skeleton as shown in III using a microchannel reaction device, using 2-benzylidene-1,3-indanedione compound I and ethyl benzoyl acetate compound II as reaction raw materials, and continuously reacting and preparing using a microchannel reaction device, wherein the microchannel reaction device comprises a feed pump, a micromixer and a microreactor connected in sequence by pipelines, and the method comprises the following steps:

[0006] (1) dissolving a 2-benzylidene-1,3-indanedione compound I and a catalyst in an organic solvent to prepare a homogeneous solution A; dissolving a benzoylethyl acetate compound II and an oxidant in an organic solvent to prepare a homogeneous solution B;

[0007] (2) The homogeneous solution A and the homogeneous solution B obtained in the above step (1) are respectively pumped into a micromixer through a feed pump, and after mixing, are introduced into a microreactor for reaction;

[0008] (3) collecting the effluent of the microreactor (the organic phase), concentrating the organic phase under vacuum to obtain a crude product, and separating and purifying the crude product to obtain a dihydrofuran compound III containing a 1,3-indanedione spirocyclic skeleton;

[0009]

[0010] Wherein, R1 is selected from halogenated benzene, C1-C4 alkylbenzene, C1-C4 alkoxybenzene, nitrobenzene, furan or naphthalene; R2 is selected from halogenated benzene, C1-C4 alkylbenzene, C1-C4 alkoxybenzene, nitrobenzene, furan, thiophene, pyridine or naphthalene.

[0011] As a preference:

[0012] The R1 is selected from benzene, 4-methoxybenzene, 3-chlorobenzene, 3-nitrobenzene, furan or naphthalene; the R2 is selected from 4-methylbenzene, 4-bromobenzene, 4-nitrobenzene, furan or naphthalene.

[0013] In step (1), the organic solvent is any one or more of 1,2-dichloroethane, γ-valerolactone, tetrahydrofuran, cyclohexane, acetonitrile, ethanol, 1,4-dioxane, ethyl acetate, and water, preferably γ-valerolactone.

[0014] In step (1), the catalyst is any one or more of tetrabutylammonium iodide, potassium iodide, sodium iodide, ammonium iodide, and N-bromosuccinimide, preferably tetrabutylammonium iodide.

[0015] In step (1), the oxidant is any one or more of benzoyl peroxide, tert-butyl hydroperoxide, sodium persulfate, ammonium persulfate, 30 wt% aqueous hydrogen peroxide solution, di-tert-butyl peroxide, and tert-butyl perbenzoate, preferably di-tert-butyl peroxide.

[0016] In step (1), the concentration of compound I in homogeneous solution A is 0.1 mmol / mL; the concentration of the catalyst in homogeneous solution A is 0.01 mmol / mL to 0.04 mmol / mL; the concentration of compound II in homogeneous solution B is 0.1 mmol / mL to 0.4 mmol / mL; and the concentration of the oxidant in homogeneous solution B is 0.1 mmol / mL to 0.6 mmol / mL.

[0017] In step (2), in the homogeneous solutions A and B pumped into the micromixer, the molar ratio of compound I, catalyst, compound II, and oxidant is 1:(0.1-0.4):(1-4):(1-6), preferably 1:0.2:1.2:3.

[0018] In step (2), the pumping speeds of homogeneous solution A and homogeneous solution B are controlled so that the volume ratio of homogeneous solution A to homogeneous solution B is 1:(0.8-2); preferably, the volume ratio of homogeneous solution A to homogeneous solution B is 1:1.

[0019] In step (2), the homogeneous solutions A and B are pumped into the microchannel reactor at a flow rate of 0.2 mL / min to 1.0 mL / min, preferably 0.5 mL / min; the reaction temperature is 80°C to 120°C, preferably 120°C; the reaction residence time is 5 to 25 min, preferably 10 min.

[0020] The microchannel reaction device further comprises a receiver connected after the microreactor, and the feed pump comprises a first feed pump and a second feed pump, both of which are connected to the micromixer in parallel through a pipeline.

[0021] In step (2), the microchannel reaction device includes a first feed pump A, a second feed pump B, a micromixer, a microreactor and a receiver; wherein the first feed pump A and the second feed pump B are connected to the micromixer in parallel through a pipeline, and the micromixer, the microreactor and the receiver are connected in series in sequence, and the connection is through a pipeline. The pipeline in the microreactor is a capillary or a polytetrafluoroethylene tube, preferably a polytetrafluoroethylene tube; the reaction volume of the microchannel reactor is 5ml to 10ml, and the inner diameter of the coil of the reactor is 0.5mm to 1mm; most preferably, the reaction volume of the microchannel reactor is 10ml, and the inner diameter of the coil of the reactor is 0.5mm.

[0022] In step (3), the vacuum concentration is to remove the organic solvent by rotary evaporation, and the temperature of the rotary evaporation is 45° C.; the separation and purification includes column chromatography using a developing solvent having a ratio of petroleum ether to ethyl acetate of 5:1.

[0023] Microchannel reactor technology has gradually become a research hotspot in the field of international fine chemical technology. A microchannel reactor is a three-dimensional structural element that can be used for chemical reactions and is manufactured with a fixed matrix using special micromachining technology. Microchannel reactors usually contain very small channel sizes (equivalent diameter less than 500 μm) and channel diversity, and fluids flow, mix, and react in these channels. Therefore, this micro-structured chemical equipment has a very large specific surface area (surface area / volume). The resulting advantage is great mass transfer and heat transfer efficiency, which can achieve precise control of the reaction temperature and instantaneous mixing of the reaction materials in precise proportions. These are the keys to improving yield, selectivity, and product quality. In addition, the process in the microfluidic field reaction system is safer, energy-saving, and environmentally friendly.

[0024] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0025] (1) The present invention is the first to use 2-benzylidene-1,3-indanedione compounds as substrates to prepare new dihydrofuran containing a spirocyclic 1,3-indanedione structure. This method avoids multi-step reactions or multi-component reactions to improve atom utilization, uses non-metallic catalysts and low-toxic solvents, and the reaction conditions are greener and environmentally friendly.

[0026] (2) The microchannel reaction device used in the present invention can accelerate the reaction rate, shorten the reaction time, realize the continuous synthesis of such compounds, and has stable product quality. The reaction process is easy to control and can effectively improve the mass transfer and heat transfer effect of the reaction, improve the safety of the reaction process, and reduce the amount of wastewater discharged, thus having good industrial application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 1 is a schematic diagram of the process flow of the microchannel reaction device of the present invention (taking the preparation of compound 1 as an example);

[0028] Figure 2 is the NMR image of Example 1 of the compound of the present invention;

[0029] Figure 3 is the NMR image of Example 2 of the compound of the present invention;

[0030] Figure 4 is the NMR image of Example 3 of the compound of the present invention;

[0031] Figure 5 is the NMR image of compound Example 4 of the present invention;

[0032] Figure 6 is the NMR image of compound Example 5 of the present invention;

[0033] Figure 7 is the NMR image of compound Example 6 of the present invention;

[0034] Figure 8 is the NMR image of compound Example 7 of the present invention;

[0035] Fig. 9 is the NMR image of compound Example 8 of the present invention;

[0036] Fig.10 is the NMR image of compound Example 9 of the present invention;

[0037] Fig.11 is the NMR image of compound Example 10 of the present invention;

[0038] Fig.12 is the NMR image of compound Example 11 of the present invention;

[0039] Fig.13 is the NMR image of compound Example 12 of the present invention; DETAILED DESCRIPTION

[0040] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0041] use Figure 1 The device diagram is as follows: (1) adding solution A and solution B prepared in proportion to injection pumps a and b (first feed pump and second feed pump) respectively; (2) injecting them into the microchannel reaction device in a certain proportion through the injection pump for mixing (micromixer) and reaction (microreactor); (3) the reaction temperature of the microchannel reactor is controlled by an oil bath; (4) collecting the outflowing reaction liquid (receiver), adding saturated sodium thiosulfate to quench, and calculating the product yield by HPLC method; the product yield is measured by high performance liquid chromatography, and then separated by column chromatography to obtain the target product (unless otherwise specified, the column chromatography uses 200-300 mesh silica gel produced by Shandong Qingdao Kangyexin Pharmaceutical Silica Gel Desiccant Co., Ltd.).

[0042] Example 1

[0043] 1 mmol (0.234 g) of 2-benzylidene indene-1,3-dione and 0.2 mmol (0.074 g) of tetrabutylammonium iodide were dissolved in 10 ml of γ-valerolactone, and the resulting mixed solution was recorded as solution A; 1.2 mmol (0.23 g) of ethyl benzoylacetate and 3 mmol (0.44 g) of tert-butyl peroxide were dissolved in 10 ml of γ-valerolactone, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1, with a flow rate of 0.5 mL / min, respectively. After mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 10 mL) and reacted at 120°C for 10 min. The organic phase was obtained by discharging the microreactor, and the crude product was obtained by vacuum concentration. The crude product was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 5:1 to obtain the target product (see Table 1) with a yield of 97%. 1 HNMR (400MHz, Chloroform-d): δ8.11(d,J=7.6Hz,1H),8.01(d,J=7.2Hz,2H),7.90(t,J=7.4Hz,1H),7.81(t,J=7.4Hz,1H),7.6 3(d,J=7.6Hz,1H),7.46(q,J=8.4,6.6Hz,3H),7.18(s,3H),6.98(s,2H),4.90(s,1H),4.04-3,85(m,2H),0.89(t,J=7.1Hz,3H); 13 C NMR (100MHz, Chloroform-d): δ194.0,192.4,167.2,141.8,139.8,138.6,137.1,136.7,134.3,131.4,129.9, 129.7,128.5,128.4,128.2,127.8,126.6,124.63,123.9,104.7,88.8,60.2,58.3,13.8; HRMS(ESI-TOF):m / z calcd for C 27 H 21 O5[M+H] + 425.1384,Found 425.1378.

[0044] Example 2

[0045] 1mmol (0.264g) of 2-(4-methoxybenzylidene)-1H-indene-1,3(2H)-dione and 0.2mmol (0.074g) of tetrabutylammonium iodide were dissolved in 10ml of γ-valerolactone, and the resulting mixed solution was recorded as solution A; 1.2mmol (0.23g) of ethyl benzoylacetate and 3mmol (0.44g) of tert-butyl peroxide were dissolved in 10ml of γ-valerolactone, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1 at a flow rate of 0.5mL / min, and after mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5mm, and the volume of the polytetrafluoroethylene tube was 10mL) and reacted at 120°C for 10min. The organic phase was obtained by discharging the microreactor, and the crude product was obtained by vacuum concentration. The crude product was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 5:1 to obtain the target product (see Table 1) with a yield of 84%. 1 H NMR (400MHz, Chloroform-d): δ8.10(d,J=7.6Hz,1H),8.00(d,J=6.6Hz,2H),7.90(t,J=7.2Hz,1H),7.82(t,J=7.4Hz,1H),7.66(d,J=7.6 Hz,1H),7.51–7.41(m,3H),6.95–6.82(m,2H),6.71(d,J=8.4Hz,2H),4.85(s,1H),4.01–3.90(m,2H),3.74(s,3H),0.92(t,J=7.1Hz,3H); 13 C NMR (100MHz, Chloroform-d): δ194.3,192.8,166.4,163.6,159.1,141.9,139.9,136.7,136.3,131.1,129.8,1 29.5,128.8,128.3,127.7,124.4,123.7,113.7,105.5,89.5,60.0,58.6,55.1,13.8; HRMS(ESI-TOF):m / zcalcd for C 28 H 23 O6[M+H] + 455.1489,Found 455.1487.

[0046] Example 3

[0047] 1 mmol (0.268 g) of 2-(3-chlorobenzylidene)-1H-indene-1,3(2H)-dione and 0.2 mmol (0.074 g) of tetrabutylammonium iodide were dissolved in 10 ml of γ-valerolactone, and the resulting mixed solution was recorded as solution A; 1.2 mmol (0.23 g) of ethyl benzoylacetate and 3 mmol (0.44 g) of tert-butyl peroxide were dissolved in 10 ml of γ-valerolactone, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1 at a flow rate of 0.5 mL / min, and after mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 10 mL) and reacted at 120°C for 10 min. The organic phase was obtained by discharging the microreactor, and the crude product was obtained by vacuum concentration. The crude product was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 5:1 to obtain the target product (see Table 1) with a yield of 95%. 1 H NMR (400MHz, Chloroform-d) δ8.12(d,J=7.6Hz,1H),8.00(d,J=7.2Hz,2H),7.93(t,J=7.4Hz,1H),7.86(t,J=7.4Hz,1H),7.70( d,J=7.5Hz,1H),7.53–7.43(m,3H),7.17(t,J=9.3Hz,2H),6.94(s,2H),4.84(s,1H),4.03–3.91(m,2H),0.93(t,J=7.1Hz,3H); 13 C NMR(100MHz,Chloroform-d)δ194.0,192.4,167.2,141.8,139.8,138.6,137.1,136.7,134.3,131.4,129.9, 129.7,128.5,128.4,128.2,127.8,126.6,124.6,123.9,104.7,88.8,60.2,58.3,13.8; HRMS(ESI-TOF):m / z calcd for C 27 H 20 O5Cl[M+H] + 459.0994,Found 459.1001.

[0048] Example 4

[0049] 1mmol (0.279g) of 2-(3-nitrobenzylidene)-1H-indene-1,3(2H)-dione and 0.2mmol (0.074g) of tetrabutylammonium iodide were dissolved in 10ml of γ-valerolactone, and the resulting mixed solution was recorded as solution A; 1.2mmol (0.23g) of ethyl benzoylacetate and 3mmol (0.44g) of tert-butyl peroxide were dissolved in 10ml of γ-valerolactone, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1 at a flow rate of 0.5mL / min, and after mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5mm, and the volume of the polytetrafluoroethylene tube was 10mL) and reacted at 120°C for 10min. The organic phase was obtained by discharging the microreactor, and vacuum concentrated to obtain a crude product, which was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 5:1 to obtain the target product (see Table 1), with a yield of 96%. 1 H NMR (400MHz, Chloroform-d): δ8.15(d,J=7.6Hz,1H),8.10(d,J=7.6Hz,1H),8.00(d,J=7.6Hz,2H),7.95(d,J=7.6Hz,1H),7.8 6(t,J=7.5Hz,2H),7.67(d,J=7.6Hz,1H),7.49(dd,J=15.2,7.2Hz,5H),4.96(s,1H),4.03–3.90(m,2H),0.93(t,J=7.1Hz,3H); 13 C NMR (100MHz, Chloroform-d): δ193.59,192.4,167.7,163.1,148.0,141.5,139.7,138.9,137.3,137.2,134.7,13 1.6,129.9,129.5,128.2,127.9,124.9,123.9,123.3,123.1,104.6,88.0,60.3,57.9,13.8; HRMS(ESI-TOF):m / z calcd for C 27 H 20 NO7[M+H] + 470.1234,Found 470.1245.

[0050] Example 5

[0051] 1mmol (0.224g) of 2-(furan-2-ylmethylene)-1H-indene-1,3(2H)-dione and 0.2mmol (0.074g) of tetrabutylammonium iodide were dissolved in 10ml of γ-valerolactone, and the resulting mixed solution was recorded as solution A; 1.2mmol (0.23g) of ethyl benzoylacetate and 3mmol (0.44g) of tert-butyl peroxide were dissolved in 10ml of γ-valerolactone, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1 at a flow rate of 0.5mL / min, and after mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5mm, and the volume of the polytetrafluoroethylene tube was 10mL) and reacted at 120°C for 10min. The organic phase was obtained by discharging the microreactor, and the crude product was obtained by vacuum concentration. The crude product was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 5:1 to obtain the target product (see Table 1) with a yield of 82%. 1 H NMR (400MHz, Chloroform-d): δ8.11(d,J=6.9Hz,1H),7.96(dd,J=8.2,1.3Hz,2H),7.94–7.85(m,3H),7.49–7.41(m,3H),7. 24–7.19(m,1H),6.27(dd,J=3.2,1.8Hz,1H),6.10(d,J=3.3Hz,1H),5.00(s,1H),4.09–3.98(m,2H),1.03(t,J=7.1Hz,3H); 13 C NMR (100MHz, Chloroform-d): δ163.3,149.8,140.0,136.9,136.6,131.2,129.9,128 .5,127.7,124.5,123.8,110.8,108.8,102.7,60.2,51.5,13.9.HRMS(ESI-TOF):m / z calcd for C 25 H 19 O6[M+H] + 415.1176,Found 415.1180.

[0052] Example 6

[0053] 1mmol (0.284g) of 2-(naphthalene-2-ylmethylene)-1H-indene-1,3(2H)-dione and 0.2mmol (0.074g) of tetrabutylammonium iodide were dissolved in 10ml of γ-valerolactone, and the resulting mixed solution was recorded as solution A; 1.2mmol (0.23g) of ethyl benzoylacetate and 3mmol (0.44g) of tert-butyl peroxide were dissolved in 10ml of γ-valerolactone, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1 at a flow rate of 0.5mL / min, and after mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5mm, and the volume of the polytetrafluoroethylene tube was 10mL) and reacted at 120°C for 10min. The organic phase was obtained by discharging the microreactor, and the crude product was obtained by vacuum concentration. The crude product was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 5:1 to obtain the target product (see Table 1) with a yield of 92%. 1 H NMR (400MHz, Chloroform-d): δ8.14(d,J=7.7Hz,1H),8.06(d,J=6.8Hz,2H),7.89(t,J=7.4Hz,1H),7.79–7.67(m, 3H),7.68–7.59(m,1H),7.57–7.35(m,7H),7.20(s,1H),5.07(s,1H),3.91(q,J=7.0Hz,2H),0.85(t,J=7.1Hz,3H); 13 C NMR (100MHz, Chloroform-d): δ194.3,192.5,166.8,163.6,141.9,139.9,136.8,136.4,134.0,133.1,133.0,131.2,12 9.9,128.7,128.2,127.9,127.8,127.7,127.6,126.1,124.5,123.8,105.4,89.3,60.1,59.1,13.8; HRMS(ESI-TOF):m / z calcd for C 31 H 23 O5[M+H] + 475.1540,Found 475.1555.

[0054] Example 7

[0055] 1 mmol (0.234 g) of 2-benzylidene indene-1,3-dione and 0.2 mmol (0.074 g) of tetrabutylammonium iodide were dissolved in 10 ml of γ-valerolactone, and the resulting mixed solution was recorded as solution A; 1.2 mmol (0.247 g) of ethyl 3-p-tolyl-3-oxopropionate and 3 mmol (0.44 g) of tert-butyl peroxide were dissolved in 10 ml of γ-valerolactone, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1 at a flow rate of 0.5 mL / min, and after mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 10 mL) and reacted at 120°C for 10 min. The organic phase was obtained by discharging the microreactor, and the crude product was obtained by vacuum concentration. The crude product was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 5:1 to obtain the target product (see Table 1) with a yield of 91%. 1 H NMR (400MHz, Chloroform-d): δ8.10(d,J=7.6Hz,1H),7.90(dd,J=12.5,7.5Hz,3H),7.81(t,J=7.5Hz,1H),7.63(d,J=7.6Hz,1H) ,7.27(s,1H),7.25(s,1H),7.21–7.14(m,3H),6.97(s,2H),4.88(s,1H),3.99–3.89(m,2H),2.41(s,3H),0.89(t,J=7.1Hz,3H); 13 C NMR (100MHz, Chloroform-d): δ194.4,192.8,166.9,163.7,141.9,141.6,139.9,136.7,136.5,136.4,129.8 ,128.5,128.4,128.3,127.9,125.8,124.4,123.7,104.5,89.2,59.9,59.1,21.7,13.8; HRMS(ESI-TOF):m / z calcd for C 28 H 23 O5[M+H] + 439.1540,Found 439.1545.

[0056] Example 8

[0057] 1 mmol (0.234 g) of 2-benzylidene indene-1,3-dione and 0.2 mmol (0.074 g) of tetrabutylammonium iodide were dissolved in 10 ml of γ-valerolactone, and the resulting mixed solution was recorded as solution A; 1.2 mmol (0.284 g) of ethyl p-nitrobenzoyl acetate and 3 mmol (0.44 g) of tert-butyl peroxide were dissolved in 10 ml of γ-valerolactone, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1 at a flow rate of 0.5 mL / min, and after mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 10 mL) and reacted at 120°C for 10 min. The organic phase was obtained by discharging the microreactor, and the crude product was obtained by vacuum concentration. The crude product was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 5:1 to obtain the target product (see Table 1) with a yield of 98%. 1 HNMR (400MHz, Chloroform-d): δ8.26 (dd, J=31.8, 8.0Hz, 4H), 8.12 (d, J=7.0Hz, 1H), 7.88 (dt, J=36.8, 6.8Hz ,2H),7.64(d,J=7.1Hz,1H),7.20(s,3H),6.96(s,2H),4.94(s,1H),4.02–3.89(m,2H),0.88(t,J=6.5Hz,3H); 13 C NMR (100MHz, Chloroform-d): δ194.0,192.3,163.6,163.0,149.0,141.8,139.8,137.1,136.6,135.5,13 4.7,131.0,128.5,128.3,128.2,124.5,123.9,123.0,108.1,89.5,60.5,59.1,13.7; HRMS(ESI-TOF):m / z calcd forC 27 H 20 NO7[M+H] + 470.1234,Found 470.1233.

[0058] Example 9

[0059] 1 mmol (0.234 g) of 2-benzylidene indene-1,3-dione and 0.2 mmol (0.074 g) of tetrabutylammonium iodide were dissolved in 10 ml of γ-valerolactone, and the resulting mixed solution was recorded as solution A; 1.2 mmol (0.324 g) of ethyl 4-bromobenzoyl acetate and 3 mmol (0.44 g) of tert-butyl peroxide were dissolved in 10 ml of γ-valerolactone, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1 at a flow rate of 0.5 mL / min, and after mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 10 mL) and reacted at 120°C for 10 min. The organic phase was obtained by discharging the microreactor, and the crude product was obtained by vacuum concentration. The crude product was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 5:1 to obtain the target product (see Table 1) with a yield of 85%. 1 HNMR (400MHz, Chloroform-d): δ8.11(d,J=7.6Hz,1H),7.91(t,J=8.2Hz,3H),7.82(t,J=7.5Hz,1H),7.61(dd ,J=18.7,8.1Hz,3H),7.21–7.14(m,3H),6.96(s,2H),4.89(s,1H),4.02–3.89(m,2H),0.89(t,J=7.1Hz,3H); 13 C NMR (100MHz, Chloroform-d): δ194.2,192.5,165.4,163.4,141.8,139.8,136.9,136.5,136.1,131.4,13 1.1,128.4,128.3,128.0,127.5,125.7,124.5,123.8,105.8,89.3,60.2,59.1,13.8; HRMS(ESI-TOF):m / z calcd forC 27 H 20 O5Br[M+H] + 503.0489,Found 503.0498.

[0060] Example 10

[0061] 1 mmol (0.234 g) of 2-benzylidene indene-1,3-dione and 0.2 mmol (0.074 g) of tetrabutylammonium iodide were dissolved in 10 ml of γ-valerolactone, and the resulting mixed solution was recorded as solution A; 1.2 mmol (0.218 g) of ethyl 2-furoyl acetate and 3 mmol (0.44 g) of tert-butyl peroxide were dissolved in 10 ml of γ-valerolactone, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1 at a flow rate of 0.5 mL / min, and after mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 10 mL) and reacted at 120°C for 10 min. The organic phase was obtained by discharging the microreactor, and vacuum concentrated to obtain a crude product, which was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 5:1 to obtain the target product (see Table 1), with a yield of 89%. 1 HNMR (400MHz, Chloroform-d): δ8.10(d,J=7.6Hz,1H),7.95(d,J=3.5Hz,1H),7.90(t,J=7.4Hz,1H),7.81(t,J=7.4Hz,1H),7. 66–7.59(m,2H),7.17(s,3H),6.93(s,2H),6.61(dd,J=3.3,1.5Hz,1H),4.88(s,1H),4.05–3.91(m,2H),0.90(t,J=7.1Hz,3H); 13 C NMR (100MHz, Chloroform-d): δ194.1,192.3,163.1,155.9,144.9,143.0,141.8,139.8,136.8,136.4,13 6.3,128.4,128.3,127.9,124.4,123.7,119.3,112.3,103.5,89.3,60.0,58.6,13.8; HRMS(ESI-TOF):m / z calcd for C 25 H 19 O6[M+H] + 415.1176,Found 415.1175.

[0062] Embodiment 11

[0063] 1 mmol (0.234 g) of 2-benzylidene indene-1,3-dione and 0.2 mmol (0.074 g) of tetrabutylammonium iodide were dissolved in 10 ml of γ-valerolactone, and the resulting mixed solution was recorded as solution A; 1.2 mmol (0.291 g) of ethyl 3-(naphthalene-2-yl)-3-oxopropionate and 3 mmol (0.44 g) of tert-butyl peroxide were dissolved in 10 ml of γ-valerolactone, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1 at a flow rate of 0.5 mL / min, and after mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 10 mL) and reacted at 120°C for 10 min. The organic phase was obtained by discharging the microreactor, and vacuum concentrated to obtain a crude product, which was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 5:1 to obtain the target product (see Table 1), with a yield of 89%. 1 H NMR (400MHz, Chloroform-d): δ8.57(s,1H),8.13(d,J=7.6Hz,1H),8.07(dd,J=8.6,1.6Hz,1H),7.95–7.85(m,4H),7.85–7.78(m,1H ),7.65(d,J=7.6Hz,1H),7.59–7.49(m,2H),7.24–7.15(m,3H),7.02(s,2H),4.96(s,1H),4.03–3.90(m,2H),0.90(t,J=7.1Hz,3H); 13 C NMR (100MHz, Chloroform-d): δ194.4,192.8,166.6,163.6,141.9,139.9,136.8,136.4,136.3,134.6,132.4,130.6,129.0,12 8.4,128.0,127.7,127.6,127.2,126.4,126.3,126.0,124.5,123.7,105.5,89.4,60.1,59.2,13.8; HRMS(ESI-TOF):m / zcalcd for C 31 H 23 O5[M+H] + 475.1540,Found 475.1554.

[0064] Example 12

[0065] 1 mmol (0.264 g) of 2-(4-methoxybenzylidene)-1H-indene-1,3(2H)-dione and 0.2 mmol (0.074 g) of tetrabutylammonium iodide were dissolved in 10 ml of γ-valerolactone, and the resulting mixed solution was recorded as solution A; 1.2 mmol (0.284 g) of ethyl p-nitrobenzoyl acetate and 3 mmol (0.44 g) of tert-butyl peroxide were dissolved in 10 ml of γ-valerolactone, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1 at a flow rate of 0.5 mL / min, and after mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 10 mL) and reacted at 120°C for 10 min. The organic phase was obtained by discharging the microreactor, and vacuum concentrated to obtain a crude product, which was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 5:1 to obtain the target product (see Table 1), with a yield of 96%. 1 H NMR (400MHz, Chloroform-d): δ8.29(d,J=8.5Hz,2H),8.20(d,J=8.5Hz,2H),8.11(d,J=7.5Hz,1H),7.92(t,J=7.3Hz,1H),7.84(t,J=7. 3Hz,1H),7.67(d,J=7.5Hz,1H),6.87(s,2H),6.71(d,J=7.8Hz,2H),4.88(s,1H),4.00–3.90(m,2H),3.73(s,3H),0.91(t,J=7.0Hz,3H); 13 C NMR (100MHz, Chloroform-d): δ194.0,192.3,163.2,163.1,159.3,148.9,141.8,139.8,136.6,134.8,131. 0,129.5,127.5,124.5,123.9,122.9,113.8,108.3,89.6,60.5,58.5,55.2,13.8; HRMS(ESI-TOF):m / zcalcd for C 28 H 22 O8N[M+H] + 500.1340,Found 500.1334.

[0066] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

[0067] Table 1 Dihydrofuran compounds containing 1,3-indanedione spiro ring skeleton of the present invention

[0068]

[0069]

Claims

1. A method for synthesizing dihydrofuran containing a 1,3-indanedione spirocyclic skeleton using a microchannel reaction device, characterized in that: A 2-benzylidene-1,3-indanedione compound I and an ethyl benzoyl acetate compound II are used as reaction raw materials and continuously reacted and prepared using a microchannel reaction device, wherein the microchannel reaction device comprises a feed pump, a micromixer and a microreactor connected in sequence through pipelines. The method comprises the following steps: (1) dissolving a 2-benzylidene-1,3-indanedione compound I and a catalyst in an organic solvent to prepare a homogeneous solution A; dissolving a benzoylethyl acetate compound II and an oxidant in an organic solvent to prepare a homogeneous solution B; (2) The homogeneous solution A and the homogeneous solution B obtained in the above step (1) are respectively pumped into a micromixer by a feed pump, and after mixing, they are introduced into a microreactor for reaction; the reaction volume of the microreactor is 5 ml to 10 ml, the inner diameter of the coil of the microreactor is 0.5 mm to 1 mm, the reaction flow rate is 0.2 mL / min to 1.0 mL / min, and the reaction residence time is 5 to 25 min; the reaction temperature is 80 to 120° C.; in the homogeneous solutions A and B pumped into the micromixer, the molar ratio of compound I, catalyst, compound II, and oxidant is 1:(0.1 to 0.4):(1 to 4):(1 to 6) (3) collecting the effluent from the microreactor to obtain a dihydrofuran compound III containing a 1,3-indanedione spirocyclic skeleton; Wherein, R1 is selected from halogenated benzene, C1-C4 alkylbenzene, C1-C4 alkoxybenzene, nitrobenzene, furan or naphthalene; R2 is selected from halogenated benzene, C1-C4 alkylbenzene, C1-C4 alkoxybenzene, nitrobenzene, furan, thiophene, pyridine or naphthalene.

2. The method for synthesizing dihydrofuran containing 1,3-indenedione spirocyclic skeleton by using a microchannel reaction device according to claim 1, characterized in that: The R1 is selected from benzene, 4-methoxybenzene, 3-chlorobenzene, 3-nitrobenzene, furan or naphthalene; the R2 is selected from 4-methylbenzene, 4-bromobenzene, 4-nitrobenzene, furan or naphthalene.

3. The method for synthesizing dihydrofuran containing 1,3-indenedione spirocyclic skeleton by using a microchannel reaction device according to claim 1, characterized in that: In step (1), the organic solvent is any one or more of 1,2-dichloroethane, γ-valerolactone, tetrahydrofuran, cyclohexane, acetonitrile, ethanol, 1,4-dioxane, ethyl acetate, and water.

4. The method for synthesizing dihydrofuran containing 1,3-indenedione spirocyclic skeleton by using a microchannel reaction device according to claim 1, characterized in that: In step (1), the catalyst is any one or more of tetrabutylammonium iodide, potassium iodide, sodium iodide, ammonium iodide, and N-bromosuccinimide.

5. The method for synthesizing dihydrofuran containing 1,3-indanedione spirocyclic skeleton by using a microchannel reaction device according to claim 1, characterized in that: In step (1), the oxidant is any one or more of tert-butyl hydroperoxide, hydrogen peroxide, tert-butyl perbenzoate, potassium persulfate and di-tert-butyl peroxide.

6. The method for synthesizing dihydrofuran containing 1,3-indenedione spirocyclic skeleton by using a microchannel reaction device according to claim 1, characterized in that: In step (1), the concentration of compound I in homogeneous solution A is 0.1 mmol / mL; the concentration of the catalyst in homogeneous solution A is 0.01 mmol / mL to 0.04 mmol / mL; the concentration of compound II in homogeneous solution B is 0.1 mmol / mL to 0.4 mmol / mL; and the concentration of the oxidant in homogeneous solution B is 0.1 mmol / mL to 0.6 mmol / mL.

7. The method for synthesizing dihydrofuran containing 1,3-indenedione spirocyclic skeleton by using a microchannel reaction device according to claim 1, characterized in that: In step (2), the pumping speeds of homogeneous solution A and homogeneous solution B are controlled so that the volume ratio of homogeneous solution A to homogeneous solution B is 1:(0.8-2).

8. The method for synthesizing dihydrofuran containing 1,3-indanedione spirocyclic skeleton by using a microchannel reaction device according to claim 1, characterized in that: The microchannel reaction device comprises a feed pump, a micro mixer and a micro reactor which are sequentially connected through pipelines, and the three are connected in parallel through pipelines.

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