A method for continuously preparing ibuprofen using a microchannel module reaction device

Abstract

The present invention belongs to the technical field of photocatalytic organic chemical synthesis, and relates to a method for continuously preparing isobufenprofen using a microchannel module reaction device. Isobutylbenzene and methyl 2-bromopropionate are dissolved in a solvent to obtain a solution A; a photocatalyst and an alkali are dissolved in a solvent to obtain a solution B; solution A and solution B are respectively and simultaneously pumped into a first microstructure reactor of a microchannel module reaction device for photoreaction to obtain a first reaction liquid; the first reaction liquid obtained and an acidic aqueous solution are respectively and simultaneously pumped into a second microstructure reactor of a microchannel module reaction device for hydrolysis reaction to obtain a second reaction liquid; the second reaction liquid is washed with water, extracted, separated and purified to obtain isobufenprofen. The method for continuously preparing isobufenprofen using a microchannel module reaction device provided by the present invention has high reaction efficiency, low energy consumption, mild reaction conditions, and a safer, more efficient and green reaction process, and has great potential in later industrial applications.

Description

Technical Field

[0001] The invention belongs to the technical field of photocatalytic organic chemical synthesis and relates to a method for continuously preparing ibuprofen by utilizing a microchannel module reaction device. Background Art

[0002] Ibuprofen, also known as ibuprofen, is one of the first batch of national over-the-counter drugs. It belongs to the antipyretic and analgesic category and non-steroidal anti-inflammatory drugs. This product produces analgesic and anti-inflammatory effects by inhibiting cyclooxygenase and reducing the synthesis of prostaglandins; it has an antipyretic effect through the hypothalamic temperature regulation center. At present, when the virus is widely spread, ibuprofen has become an indispensable home treatment drug. In addition, ibuprofen is also suitable for the treatment of inflammations such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis due to its strong anti-inflammatory and analgesic effects and few side effects.

[0003] At present, the Boots and BHC methods have been industrialized for the production of ibuprofen, but they have defects such as low reaction efficiency, high energy consumption, and complex reaction system. In addition, there are also reported Grignard reaction method, cyanide method, epoxy carboxylate method, etc. These synthetic routes have various problems, such as the need for precious metal catalysts, low atomic utilization, many by-products, serious pollution, and potential safety hazards, which greatly restrict these synthetic methods and do not meet the requirements of the development of green chemistry today. Therefore, it is of great significance to develop a new method for the synthesis of ibuprofen with mild conditions and high efficiency. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a method for realizing efficient continuous synthesis of isobutylbenzene and methyl 2-bromopropionate using microchannel technology as raw materials through photocatalytic reaction and subsequent hydrolysis reaction.

[0005] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0006] The present invention discloses a method for continuously preparing ibuprofen using a microchannel module reaction device, comprising the following steps:

[0007] (1) dissolving isobutylbenzene and methyl 2-bromopropionate in a solvent to obtain a solution A; dissolving a photocatalyst and a base in a solvent to obtain a solution B; pumping the solution A and the solution B into a first micromixer of a microchannel module reaction device to mix, and then pumping the solution A and the solution B into a first microstructure reactor of the microchannel module reaction device to perform a photoreaction to obtain a first reaction liquid;

[0008] (2) the first reaction liquid obtained in step (1) and the acidic aqueous solution are respectively pumped into the second micro mixer of the microchannel module reaction device for mixing, and then pumped into the second microstructured reactor of the microchannel module reaction device for hydrolysis reaction to obtain a second reaction liquid;

[0009] (3) The second reaction liquid obtained in step (2) is washed with water, extracted, separated and purified to obtain ibuprofen.

[0010] In some embodiments, in step (1), the solvent is any one or a combination of acetonitrile, dichloromethane, 1,2-dichloroethane, methanol, toluene, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide and water, preferably a mixture of acetonitrile, dimethyl sulfoxide and water in any proportion, further preferably a mixture of acetonitrile and water in a volume ratio of 7-8:2-3, and more preferably a mixture of acetonitrile and water in a volume ratio of 8:2.

[0011] In some embodiments, in step (1), the photocatalyst is any one or a combination of Eosin Y, terpyridine ruthenium chloride hexahydrate (Ru(bpy)3Cl2), tris(2-phenylpyridine) iridium (Ir(ppy)3), di[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) salt (Ir[dF(CF3)(ppy)]2(dtbbpy)•PF6), Rose Bengal, 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (4-CzIPN), methylene blue trihydrate and rhodamine B, preferably Eosin Y or tris(2-phenylpyridine) iridium (Ir(ppy)3), and more preferably Eosin Y.

[0012] In some embodiments, in step (1), the base is any one or a combination of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), triethanolamine (TEA), 4-dimethylaminopyridine (DMAP), N,N-diisopropylethylamine (DIPEA), tetramethylguanidine (TMG), tetramethylethylenediamine (TMEDA), potassium carbonate (K2CO3), cesium carbonate (Cs2CO3) and potassium phosphate (K3PO4), preferably N,N-diisopropylethylamine (DIPEA) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and more preferably N,N-diisopropylethylamine (DIPEA).

[0013] In some embodiments, in step (1), the concentration of isobutylbenzene in the solution A is 0.01-0.10 mmol / mL, preferably 0.02-0.03 mmol / mL, and more preferably 0.02 mmol / mL; the concentration of methyl 2-bromopropionate in the solution A is 0.01-0.10 mmol / mL, preferably 0.02-0.03 mmol / mL, and more preferably 0.03 mmol / mL; the concentration of the photocatalyst in the solution B is 0.001-0.01 mmol / mL, and preferably 0.001 mmol / mL; the concentration of the base in the solution B is 0.01-0.10 mmol / mL, and preferably 0.03 mmol / mL; the molar ratio of isobutylbenzene to the base is 1:0.5-1.5, preferably 1:1-1.5, and more preferably 1:1 or 1:1.5, and more preferably 1:1.5.

[0014] In some embodiments, in step (1), the flow rate at which solution A is pumped into the first micromixer of the microchannel module reaction device is 0.2~4 mL / min, preferably 0.5~2 mL / min, and more preferably 1 mL / min; the flow rate at which solution B is pumped into the first micromixer of the microchannel module reaction device is 0.2~4 mL / min, preferably 0.5~2 mL / min, and more preferably 1 mL / min.

[0015] In some embodiments, in step (1), the light source of the photoreaction is blue light, the reaction temperature is room temperature, the reaction residence time is 0.5 to 10 min, preferably 5 to 10 min, and more preferably 5 min; the wavelength of the blue light is 390 to 470 nm, preferably 410 to 460 nm, and more preferably 450 to 460 nm.

[0016] In some embodiments, in step (2), the acidic aqueous solution is any one or a combination of hydrochloric acid aqueous solution, hydrobromic acid solution, sulfuric acid aqueous solution, acetic acid aqueous solution and trifluoroacetic acid aqueous solution, preferably hydrochloric acid aqueous solution or trifluoroacetic acid aqueous solution, and more preferably hydrochloric acid aqueous solution.

[0017] In some embodiments, in step (2), the concentration of the acidic aqueous solution is 10-40 wt%, preferably 20 wt%.

[0018] In some embodiments, in step (2), the flow rate at which the first reaction liquid is pumped into the second micromixer of the microchannel module reaction device is 0.5~5 mL / min, preferably 1~4 mL / min, and more preferably 2 mL / min; the flow rate at which the acidic aqueous solution is pumped into the second micromixer of the microchannel module reaction device is 0.25~5 mL / min, preferably 0.25~2 mL / min, and more preferably 0.5 mL / min.

[0019] In some embodiments, in step (2), the hydrolysis reaction has a reaction temperature of 20-80°C, preferably 40-70°C, and more preferably 60°C, and a reaction residence time of 0.5-10 min, preferably 4 min.

[0020] In some embodiments, the microchannel module reaction device includes a light source, a first raw material storage tank, a second raw material storage tank, a third raw material storage tank, a first micromixer, a second micromixer, a first microstructure reactor, a second microstructure reactor and a product collector; the first raw material storage tank and the second raw material storage tank are connected in parallel and connected to the first micromixer through a pipeline; the first micromixer is connected to the first microstructure reactor through a pipeline; the third raw material storage tank and the first microstructure reactor are connected in parallel and connected to the second micromixer through a pipeline; the second micromixer, the second microstructure reactor and the product collector are connected in series in sequence through pipelines; wherein the light source is a blue LED light strip with a diameter of 12 cm; the light source is arranged on the periphery of the first microstructure reactor, and its illumination range covers the first microstructure reactor, and the first microstructure reactor is 2 cm away from the light strip.

[0021] In some embodiments, the volume of the first microstructured reactor is 5-50 mL, preferably 10 mL.

[0022] In some embodiments, the volume of the second microstructured reactor is 5-50 mL, preferably 5-24 mL, and more preferably 10 mL.

[0023] In some embodiments, the micromixer is a Y-shaped tube with an inner diameter of 6 mm and an outer diameter of 9 mm, and is made of polytetrafluoroethylene.

[0024] In some embodiments, the connecting pipes in the above-mentioned microchannel module reaction device adopt capillaries with a diameter of 1 mm.

[0025] In some embodiments, the inner diameter of the coils of the first microstructure reactor and the second microstructure reactor is 1 mm.

[0026] In some embodiments, the reaction temperature of the second microstructure reactor is controlled by an oil bath.

[0027] In some embodiments, a feed pump is provided between the raw material storage tank and the micro-mixer, and the feed pump is a syringe pump with a model of TYD01-01-CE.

[0028] Beneficial effects:

[0029] Compared with the prior art, the method for continuously preparing isobufenprofen using a microchannel module reaction device provided by the present invention uses isobutylbenzene and methyl 2-bromopropionate as raw materials, and realizes efficient and continuous synthesis of isobufenprofen through a photocatalytic reaction and a subsequent hydrolysis reaction; the method has high reaction efficiency, low energy consumption, mild reaction conditions, and a safer, more efficient and environmentally friendly reaction process, and has great potential for later industrial applications. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more clear.

[0031] Figure 1 The figure is a synthetic route diagram of ibuprofen of the present invention.

[0032] Figure 2 This is a diagram of the microchannel module reaction device of the present invention.

[0033] Figure 3 This is the H NMR spectrum of ibuprofen.

[0034] Figure 4 This is the NMR carbon spectrum of ibuprofen.

[0035] Figure 5 This is a high-resolution mass spectrum of ibuprofen. DETAILED DESCRIPTION

[0036] 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.

[0037] Figure 2 The microchannel module reaction device diagram of the present invention is as follows: Figure 2As shown, the microchannel module reaction device includes a first raw material storage tank, a second raw material storage tank, a third raw material storage tank, a first micromixer, a second micromixer, a first microstructure reactor, a second microstructure reactor and a product collector; the first raw material storage tank and the second raw material storage tank are connected in parallel and connected to the first micromixer through a pipeline; the first micromixer is connected to the first microstructure reactor through a pipeline; the third raw material storage tank and the first microstructure reactor are connected in parallel and connected to the second micromixer through a pipeline; the second micromixer, the second microstructure reactor and the product collector are connected in series in sequence through pipelines.

[0038] The light source is a blue LED light strip with a diameter of 12 cm. The light source is arranged outside the first microstructure reactor, and its illumination range covers the first microstructure reactor. The first microstructure reactor is 2 cm away from the light strip.

[0039] Among them, the volume of the first microstructured reactor is 10 mL.

[0040] The volume of the second microstructured reactor is 5 mL, 10 mL or 24 mL.

[0041] The micromixer is a Y-shaped tube with an inner diameter of 6 mm and an outer diameter of 9 mm, and is made of polytetrafluoroethylene.

[0042] The connecting pipes in the microchannel module reaction device adopt capillaries with a diameter of 1 mm.

[0043] Among them, the inner diameter of the coils of the first microstructure reactor and the second microstructure reactor is 1 mm.

[0044] The reaction temperature of the second microstructure reactor is controlled by an oil bath.

[0045] Among them, a feed pump is arranged between the raw material storage tank and the micro mixer, and the feed pump is a syringe pump with model TYD01-01-CE.

[0046] Embodiment 1:

[0047] (1) Dissolve 0.2 mmol of isobutylbenzene and 0.3 mmol of methyl 2-bromopropionate in 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水 = 8:2) to prepare a homogeneous solution A and place it in the first raw material storage tank. Then, 0.3 mmol DIPEA and 0.01 mmol Eosin Y were dissolved in 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水= 8:2) to make a homogeneous solution B and then place it in the second raw material storage tank. Solution A and solution B were pumped into the first micro mixer of the microchannel module reaction device at a flow volume ratio of 1:1 at a flow rate of 1 mL / min, respectively. After being fully mixed, they were injected into the first microstructured reactor (10 mL) of the microchannel module reaction device, and photoreaction was carried out at room temperature under 450-460 nm blue light for 5 min to obtain the first reaction solution.

[0048] (2) Then, the first reaction liquid (2 mL / min) obtained in step (1) and the 20 wt.% hydrochloric acid aqueous solution (0.5 mL / min) in the third raw material storage tank were pumped into the second micromixer of the microchannel module reaction device at the same time, and after being fully mixed, they were injected into the second microstructured reactor (10 mL) of the microchannel module reaction device, and reacted at 60°C for 4 min to obtain a second reaction liquid.

[0049] (3) The second reaction liquid obtained in step (2) is subjected to extraction, water washing and column chromatography separation and purification to obtain ibuprofen with a yield of 86%.

[0050] The synthetic route of ibuprofen is as follows Figure 1 As shown, the nuclear magnetic hydrogen spectrum of ibuprofen is as follows Figure 3 As shown, the NMR carbon spectrum of ibuprofen is as follows Figure 4 As shown, the high-resolution mass spectrum of ibuprofen is as follows Figure 5 The H-NMR spectrum, C-NMR spectrum and mass spectrum data of ibuprofen are as follows.

[0051] 1 H NMR (400 MHz, Chloroform- d ) δ 7.22 (d, J = 7.8 Hz, 2H), 7.10 (d, J =7.8 Hz, 2H), 3.71 (q, J = 7.1 Hz, 1H), 2.45 (d, J = 7.1 Hz, 2H), 1.89-1.79(m,1H),1.50 (d, J = 7.2 Hz, 3H), 0.90 (d, J = 6.6 Hz, 6H) ppm; 13 C NMR (100 MHz, Chloroform- d) δ 180.3, 141.0, 137.1, 129.6, 127.4, 45.2, 45.0, 30.3, 22.5,18.3 ppm; HRMS (ESI-TOF): m / z calcd for C 13 H 19 O2[M+H]+ 207.1380, found207.1413.

[0052] Embodiment 2:

[0053] (1) Dissolve 0.2 mmol of isobutylbenzene and 0.3 mmol of methyl 2-bromopropionate in 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水 = 8:2) to prepare a homogeneous solution A and place it in the first raw material storage tank. Then, 0.3 mmol DBU and 0.01 mmol Eosin Y were dissolved in 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水 = 8:2) to make a homogeneous solution B and then place it in the second raw material storage tank. Solution A and solution B were pumped into the first micro mixer of the microchannel module reaction device at a flow volume ratio of 1:1 at a flow rate of 1 mL / min, respectively. After being fully mixed, they were injected into the first microstructured reactor (10 mL) of the microchannel module reaction device, and photoreaction was carried out at room temperature under 450-460 nm blue light for 5 min to obtain the first reaction solution.

[0054] (2) Then, the first reaction liquid (2 mL / min) obtained in step (1) and the 20 wt.% hydrochloric acid aqueous solution (0.5 mL / min) in the third raw material storage tank were pumped into the second micromixer of the microchannel module reaction device at the same time, and after being fully mixed, they were injected into the second microstructured reactor (10 mL) of the microchannel module reaction device, and reacted at 60°C for 4 min to obtain a second reaction liquid.

[0055] (3) The second reaction liquid obtained in step (2) is subjected to extraction, water washing and column chromatography separation and purification to obtain ibuprofen with a yield of 71%.

[0056] Embodiment 3:

[0057] (1) Dissolve 0.2 mmol of isobutylbenzene and 0.3 mmol of methyl 2-bromopropionate in 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水= 8:2) to prepare a homogeneous solution A and place it in the first raw material storage tank. Then, 0.3 mmol DIPEA and 0.01 mmol Ir(ppy)3 were dissolved in 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水 = 8:2) to make a homogeneous solution B and then place it in the second raw material storage tank. Solution A and solution B were pumped into the first micro mixer of the microchannel module reaction device at a flow volume ratio of 1:1 at a flow rate of 1 mL / min, respectively. After being fully mixed, they were injected into the first microstructured reactor (10 mL) of the microchannel module reaction device, and photoreaction was carried out at room temperature under 450-460 nm blue light for 5 min to obtain the first reaction solution.

[0058] (2) Then, the first reaction liquid (2 mL / min) obtained in step (1) and the 20 wt.% hydrochloric acid aqueous solution (0.5 mL / min) in the third raw material storage tank were pumped into the second micromixer of the microchannel module reaction device at the same time, and after being fully mixed, they were injected into the second microstructured reactor (10 mL) of the microchannel module reaction device, and reacted at 60°C for 4 min to obtain a second reaction liquid.

[0059] (3) The second reaction liquid obtained in step (2) is subjected to extraction, water washing and column chromatography separation and purification to obtain ibuprofen with a yield of 65%.

[0060] Embodiment 4:

[0061] (1) Dissolve 0.2 mmol of isobutylbenzene and 0.3 mmol of methyl 2-bromopropionate in 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水 = 7:3) to prepare a homogeneous solution A and place it in the first raw material storage tank. Then, 0.3 mmol DIPEA and 0.01 mmol Eosin Y were dissolved in 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水 = 7:3) to prepare a homogeneous solution B and place it in the second raw material storage tank. Solution A and solution B were pumped into the first micro mixer of the microchannel module reaction device at a flow volume ratio of 1:1 at a flow rate of 1 mL / min, respectively. After being fully mixed, they were injected into the first microstructured reactor (10 mL) of the microchannel module reaction device, and photoreaction was carried out at room temperature under 450-460 nm blue light for 5 min to obtain the first reaction solution.

[0062] (2) Then, the first reaction liquid (2 mL / min) obtained in step (1) and the 20 wt.% hydrochloric acid aqueous solution (0.5 mL / min) in the third raw material storage tank were pumped into the second micromixer of the microchannel module reaction device at the same time, and after being fully mixed, they were injected into the second microstructured reactor (10 mL) of the microchannel module reaction device, and reacted at 60°C for 4 min to obtain a second reaction liquid.

[0063] (3) The second reaction liquid obtained in step (2) is subjected to extraction, water washing and column chromatography separation and purification to obtain ibuprofen with a yield of 80%.

[0064] Embodiment 5:

[0065] (1) Dissolve 0.2 mmol of isobutylbenzene and 0.3 mmol of methyl 2-bromopropionate in 10 mL of a mixed solvent of dimethyl sulfoxide and water (V 二甲基亚砜 :V 水 = 8:2) to prepare a homogeneous solution A and place it in the first raw material storage tank. Then, 0.3 mmol DIPEA and 0.01 mmol Eosin Y were dissolved in 10 mL of a mixed solvent of dimethyl sulfoxide and water (V 二甲基亚砜 :V 水 = 8:2) to make a homogeneous solution B and then place it in the second raw material storage tank. Solution A and solution B were pumped into the first micro mixer of the microchannel module reaction device at a flow volume ratio of 1:1 at a flow rate of 1 mL / min, respectively. After being fully mixed, they were injected into the first microstructured reactor (10 mL) of the microchannel module reaction device, and photoreaction was carried out at room temperature under 450-460 nm blue light for 5 minutes to obtain the first reaction solution.

[0066] (2) Then, the first reaction liquid (2 mL / min) obtained in step (1) and the 20 wt.% hydrochloric acid aqueous solution (0.5 mL / min) in the third raw material storage tank were pumped into the second micromixer of the microchannel module reaction device at the same time, and after being fully mixed, they were injected into the second microstructured reactor (10 mL) of the microchannel module reaction device, and reacted at 60°C for 4 min to obtain a second reaction liquid.

[0067] (3) The second reaction liquid obtained in step (2) is subjected to extraction, water washing and column chromatography separation and purification to obtain ibuprofen with a yield of 60%.

[0068] Embodiment 6:

[0069] (1) Dissolve 0.2 mmol of isobutylbenzene and 0.3 mmol of methyl 2-bromopropionate in 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水= 8:2) to prepare a homogeneous solution A and place it in the first raw material storage tank. Then, 0.3 mmol DIPEA and 0.01 mmol Eosin Y were dissolved in 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水 = 8:2) to make a homogeneous solution B and then place it in the second raw material storage tank. Solution A and solution B were pumped into the first micro mixer of the microchannel module reaction device at a flow volume ratio of 1:1 at a flow rate of 0.5 mL / min, respectively. After being fully mixed, they were injected into the first microstructured reactor (10 mL) of the microchannel module reaction device, and photoreaction was carried out at room temperature under 450-460 nm blue light for 10 min to obtain the first reaction solution.

[0070] (2) Then, the first reaction liquid (1 mL / min) obtained in step (1) and the 20 wt.% hydrochloric acid aqueous solution (0.25 mL / min) in the third raw material storage tank were pumped into the second micromixer of the microchannel module reaction device at the same time, and after being fully mixed, they were injected into the second microstructured reactor (5 mL) of the microchannel module reaction device, and reacted at 60°C for 4 min to obtain a second reaction liquid.

[0071] (3) The second reaction liquid obtained in step (2) is subjected to extraction, water washing and column chromatography separation and purification to obtain ibuprofen with a yield of 79%.

[0072] Embodiment 7:

[0073] (1) Dissolve 0.2 mmol of isobutylbenzene and 0.3 mmol of methyl 2-bromopropionate in 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水 = 8:2) to prepare a homogeneous solution A and place it in the first raw material storage tank. Then, 0.3 mmol DIPEA and 0.01 mmol Eosin Y were dissolved in 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水 = 8:2) to make a homogeneous solution B and then place it in the second raw material storage tank. Solution A and solution B were pumped into the first micro mixer of the microchannel module reaction device at a flow volume ratio of 1:1 at a flow rate of 2 mL / min, respectively. After being fully mixed, they were injected into the first microstructured reactor (10 mL) of the microchannel module reaction device, and photoreaction was carried out at room temperature and 450-460 nm blue light for 2.5 min to obtain the first reaction solution.

[0074] (2) Then, the first reaction liquid (4 mL / min) obtained in step (1) and the 20 wt.% trifluoroacetic acid aqueous solution (2 mL / min) in the third raw material storage tank were pumped into the second micromixer of the microchannel module reaction device at the same time, and after being fully mixed, they were injected into the second microstructured reactor (24 mL) of the microchannel module reaction device, and reacted at 60°C for 4 min to obtain a second reaction liquid.

[0075] (3) The second reaction liquid obtained in step (2) is subjected to extraction, water washing and column chromatography separation and purification to obtain ibuprofen with a yield of 58%.

[0076] Embodiment 8:

[0077] (1) Dissolve 0.2 mmol of isobutylbenzene and 0.3 mmol of methyl 2-bromopropionate in 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水 = 8:2) to prepare a homogeneous solution A and place it in the first raw material storage tank. Then, 0.3 mmol DIPEA and 0.01 mmol Eosin Y were dissolved in 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水 = 8:2) to make a homogeneous solution B and then place it in the second raw material storage tank. Solution A and solution B were pumped into the first micro mixer of the microchannel module reaction device at a flow volume ratio of 1:1 at a flow rate of 1 mL / min, respectively. After being fully mixed, they were injected into the first microstructured reactor (10 mL) of the microchannel module reaction device, and photoreaction was carried out at room temperature and 410-420 nm blue light for 5 min to obtain the first reaction solution.

[0078] (2) Then, the first reaction liquid (2 mL / min) obtained in step (1) and the 20 wt.% hydrochloric acid aqueous solution (0.5 mL / min) in the third raw material storage tank were pumped into the second micromixer of the microchannel module reaction device at the same time, and after being fully mixed, they were injected into the second microstructured reactor (10 mL) of the microchannel module reaction device, and reacted at 60°C for 4 min to obtain a second reaction liquid.

[0079] (3) The second reaction liquid obtained in step (2) is subjected to extraction, water washing and column chromatography separation and purification to obtain ibuprofen with a yield of 65%.

[0080] Embodiment 9:

[0081] (1) Dissolve 0.2 mmol of isobutylbenzene and 0.3 mmol of methyl 2-bromopropionate in 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水= 8:2) to prepare a homogeneous solution A and place it in the first raw material storage tank. Then, 0.3 mmol DIPEA and 0.01 mmol Eosin Y were dissolved in 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水 = 8:2) to make a homogeneous solution B and then place it in the second raw material storage tank. Solution A and solution B were pumped into the first micro mixer of the microchannel module reaction device at a flow volume ratio of 1:1 at a flow rate of 1 mL / min, respectively. After being fully mixed, they were injected into the first microstructured reactor (10 mL) of the microchannel module reaction device, and photoreaction was carried out at room temperature under 450-460 nm blue light for 5 min to obtain the first reaction solution.

[0082] (2) Then, the first reaction liquid (2 mL / min) obtained in step (1) and the 20 wt.% hydrochloric acid aqueous solution (0.5 mL / min) in the third raw material storage tank were pumped into the second micromixer of the microchannel module reaction device at the same time, and after being fully mixed, they were injected into the second microstructured reactor (10 mL) of the microchannel module reaction device, and reacted at 40°C for 4 min to obtain a second reaction liquid.

[0083] (3) The second reaction liquid obtained in step (2) is subjected to extraction, water washing and column chromatography separation and purification to obtain ibuprofen with a yield of 59%.

[0084] Embodiment 10:

[0085] (1) Dissolve 0.3 mmol of isobutylbenzene and 0.2 mmol of methyl 2-bromopropionate in 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水 = 8:2) to prepare a homogeneous solution A and place it in the first raw material storage tank. Then, 0.3 mmol DIPEA and 0.01 mmol Eosin Y were dissolved in 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水 = 8:2) to make a homogeneous solution B and then place it in the second raw material storage tank. Solution A and solution B were pumped into the first micro mixer of the microchannel module reaction device at a flow volume ratio of 1:1 at a flow rate of 1 mL / min, respectively. After being fully mixed, they were injected into the first microstructured reactor (10 mL) of the microchannel module reaction device, and photoreaction was carried out at room temperature under 450-460 nm blue light for 5 min to obtain the first reaction solution.

[0086] (2) Then, the first reaction liquid (2 mL / min) obtained in step (1) and the 20 wt.% hydrochloric acid aqueous solution (0.5 mL / min) in the third raw material storage tank were pumped into the second micromixer of the microchannel module reaction device at the same time, and after being fully mixed, they were injected into the second microstructured reactor (10 mL) of the microchannel module reaction device, and reacted at 60°C for 4 min to obtain a second reaction liquid.

[0087] (3) The second reaction liquid obtained in step (2) is subjected to extraction, water washing and column chromatography separation and purification to obtain ibuprofen with a yield of 76%.

[0088] Embodiment 11:

[0089] (1) Dissolve 0.2 mmol of isobutylbenzene and 0.3 mmol of methyl 2-bromopropionate in 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水 = 8:2) to prepare a homogeneous solution A and place it in the first raw material storage tank. Then, 0.3 mmol DIPEA and 0.01 mmol Eosin Y were dissolved in 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水 = 8:2) to make a homogeneous solution B and then place it in the second raw material storage tank. Solution A and solution B were pumped into the first micro mixer of the microchannel module reaction device at a flow volume ratio of 1:1 at a flow rate of 1 mL / min, respectively. After being fully mixed, they were injected into the first microstructured reactor (10 mL) of the microchannel module reaction device, and photoreaction was carried out at room temperature under 450-460 nm blue light for 5 min to obtain the first reaction solution.

[0090] (2) Then, the first reaction liquid (2 mL / min) obtained in step (1) and the 20 wt.% hydrochloric acid aqueous solution (0.5 mL / min) in the third raw material storage tank were pumped into the second micromixer of the microchannel module reaction device at the same time, and after being fully mixed, they were injected into the second microstructured reactor (10 mL) of the microchannel module reaction device, and reacted at 70°C for 4 min to obtain a second reaction liquid.

[0091] (3) The second reaction liquid obtained in step (2) is subjected to extraction, water washing and column chromatography separation and purification to obtain ibuprofen with a yield of 84%.

[0092] Comparative Example 1:

[0093] 0.2 mmol of isobutylbenzene, 0.3 mmol of methyl 2-bromopropionate, 0.3 mmol of DIPEA and 0.01 mmol of Eosin Y were added to the photoreaction tube in sequence. After nitrogen protection for three times, 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水 =8:2), and then mixed thoroughly to form a homogeneous solution. Then, the mixture was reacted for 12 h at room temperature under the irradiation of a 450-460 nm blue light strip. After the reaction, the obtained reaction solution was mixed with 10 mL of a 20 wt.% aqueous hydrochloric acid solution in an oil bath at 60°C for 12 h. After the reaction, the reaction solution was collected and extracted, washed with water, and purified by column chromatography to obtain isobufenprofen with a yield of 51%.

[0094] Comparative Example 2: No light source is used during the preparation process

[0095] (1) Dissolve 0.2 mmol of isobutylbenzene and 0.3 mmol of methyl 2-bromopropionate in 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水 = 8:2) to prepare a homogeneous solution A and place it in the first raw material storage tank. Then, 0.3 mmol DIPEA and 0.01 mmol Eosin Y were dissolved in 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水 = 8:2) to prepare a homogeneous solution B and place it in the second raw material storage tank. Solution A and solution B were pumped into the first micro mixer of the microchannel module reaction device at a flow volume ratio of 1:1 at a flow rate of 1 mL / min, respectively. After being fully mixed, they were injected into the first microstructured reactor (10 mL) of the microchannel module reaction device without blue light strip irradiation, and reacted at room temperature for 5 min to obtain the first reaction solution.

[0096] (2) Then, the first reaction liquid (2 mL / min) obtained in step (1) and the 20 wt.% hydrochloric acid aqueous solution (0.5 mL / min) in the third raw material storage tank were pumped into the second micromixer of the microchannel module reaction device at the same time, and after being fully mixed, they were injected into the second microstructured reactor (10 mL) of the microchannel module reaction device, and reacted at 60°C for 4 min to obtain a second reaction liquid.

[0097] (3) The second reaction liquid obtained in step (2) is subjected to extraction, water washing and column chromatography separation and purification to obtain ibuprofen with a yield of 0%.

[0098] Comparative Example 3: No photocatalyst was added during the preparation process

[0099] (1) Dissolve 0.2 mmol of isobutylbenzene and 0.3 mmol of methyl 2-bromopropionate in 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水 = 8:2) to prepare a homogeneous solution A and place it in the first raw material storage tank. Then, 0.3 mmol DIPEA was dissolved in 10 mL of a mixed solvent of acetonitrile and water (V 乙腈 :V 水 = 8:2) to make a homogeneous solution B and then place it in the second raw material storage tank. Solution A and solution B were pumped into the first micro mixer of the microchannel module reaction device at a flow volume ratio of 1:1 at a flow rate of 1 mL / min, respectively. After being fully mixed, they were injected into the first microstructured reactor (10 mL) of the microchannel module reaction device, and photoreaction was carried out at room temperature under 450-460 nm blue light for 5 min to obtain the first reaction solution.

[0100] (2) Then, the first reaction liquid (2 mL / min) obtained in step (1) and the 20 wt.% hydrochloric acid aqueous solution (0.5 mL / min) in the third raw material storage tank were pumped into the second micromixer of the microchannel module reaction device at the same time, and after being fully mixed, they were injected into the second microstructured reactor (10 mL) of the microchannel module reaction device, and reacted at 60°C for 4 min to obtain a second reaction liquid.

[0101] (3) The second reaction liquid obtained in step (2) is subjected to extraction, water washing and column chromatography separation and purification to obtain ibuprofen with a yield of 13%.

[0102] The present invention provides a method and idea for continuously preparing ibuprofen using a microchannel module reaction device. There are many methods and approaches to implement the technical solution. The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, 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 scope of protection of the present invention. All components not specified in this embodiment can be implemented by existing technologies.

Claims

1. A method for continuously preparing ibuprofen using a microchannel module reaction device, characterized in that: The steps include: (1) dissolving isobutylbenzene and methyl 2-bromopropionate in a solvent to obtain a solution A; dissolving a photocatalyst and a base in a solvent to obtain a solution B; pumping the solution A and the solution B into a first micromixer of a microchannel module reaction device to mix, and then pumping the solution A and the solution B into a first microstructure reactor of the microchannel module reaction device to perform a photoreaction to obtain a first reaction liquid; (2) the first reaction liquid obtained in step (1) and the acidic aqueous solution are respectively pumped into the second micro mixer of the microchannel module reaction device for mixing, and then pumped into the second microstructured reactor of the microchannel module reaction device for hydrolysis reaction to obtain a second reaction liquid; (3) washing, extracting, separating and purifying the second reaction liquid obtained in step (2) to obtain ibuprofen; The photocatalyst is eosin Y or tris(2-phenylpyridine)iridium; The base is 1,8-diazabicyclo[5.4.0]undec-7-ene or N,N-diisopropylethylamine; In step (1), the light source of the photoreaction is blue light, and the reaction temperature is room temperature; the wavelength of the blue light is 390-470 nm.

2. The method according to claim 1, characterized in that In step (1), the solvent is any one or a combination of acetonitrile, dichloromethane, 1,2-dichloroethane, methanol, toluene, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide and water.

3. The method according to claim 1, characterized in that In step (1), the concentration of isobutylbenzene in the solution A is 0.01-0.10 mmol / mL; the concentration of methyl 2-bromopropionate in the solution A is 0.01-0.10 mmol / mL; the concentration of the photocatalyst in the solution B is 0.001-0.01 mmol / mL; the concentration of the alkali in the solution B is 0.01-0.10 mmol / mL; and the molar ratio of the isobutylbenzene to the alkali is 1:0.5-1.

5.

4. The method according to claim 1, characterized in that: In step (1), the flow rate of the solution A pumped into the first micromixer of the microchannel module reaction device is 0.2-4 mL / min; the flow rate of the solution B pumped into the first micromixer of the microchannel module reaction device is 0.2-4 mL / min.

5. The method according to claim 1, characterized in that: In step (1), the light reaction has a reaction residence time of 0.5 to 10 min.

6. The method according to claim 1, characterized in that In step (2), the acidic aqueous solution is any one or a combination of hydrochloric acid aqueous solution, hydrobromic acid solution, sulfuric acid aqueous solution, acetic acid aqueous solution and trifluoroacetic acid aqueous solution; the concentration of the acidic aqueous solution is 10-40 wt%.

7. The method according to claim 1, characterized in that In step (2), the flow rate of the first reaction liquid pumped into the second micromixer of the microchannel module reaction device is 0.5~5 mL / min; the flow rate of the acidic aqueous solution pumped into the second micromixer of the microchannel module reaction device is 0.25~5 mL / min; the hydrolysis reaction, the reaction temperature is 20~80°C, and the reaction residence time is 0.5~10 min.

8. The method according to claim 1, characterized in that The microchannel module reaction device includes a light source, a first raw material storage tank, a second raw material storage tank, a third raw material storage tank, a first micromixer, a second micromixer, a first microstructure reactor, a second microstructure reactor and a product collector; the first raw material storage tank and the second raw material storage tank are connected in parallel to the first micromixer through a pipeline; the first micromixer is connected to the first microstructure reactor through a pipeline; the third raw material storage tank and the first microstructure reactor are connected in parallel to the second micromixer through a pipeline; the second micromixer, the second microstructure reactor and the product collector are connected in series in sequence through pipelines; wherein the light source is a blue LED light strip with a diameter of 12 cm; the light source is arranged on the periphery of the first microstructure reactor, and its illumination range covers the first microstructure reactor, and the first microstructure reactor is 2 cm away from the light strip.

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