Continuous flow synthesis method of cyclopropane compound promoted by visible light

Abstract

The invention discloses a visible light promoted continuous flow synthesis method of a cyclopropane compound as shown in a formula I. The method comprises the following steps: an olefin compound as shown in a formula II, a cyclopropanation reagent as shown in a formula III, a photocatalyst and an organic solvent enter a reactor, and the cyclopropane compound is obtained under the action of illumination; in the formula, R1 is independently a phenyl group, a 4-fluorophenyl group, a methyl group or a hydrogen group; r2 is independently a trifluoromethyl group, an ethyl ester group or hydrogen; and R3 is independently a cyano group, a methyl ester group, an ethyl ester group, a benzoyl group, a phenyl group, a trifluoromethyl group, an alkoxyphenyl group and hydrogen. By optimizing reaction conditions such as a cyclopropanation reagent, a solvent and the like, a photocatalytic reaction is combined with a continuous flow mode, so that the reaction time is greatly shortened, the reaction has better universality at low temperature, and the yield and the scale of the cyclopropane compound are improved.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a photocatalytic organic synthesis and a continuous flow reaction, and specifically relates to a visible light-promoted continuous flow synthesis method of cyclopropane compounds. Background Art

[0002] Cyclopropane is the smallest cyclic compound. It is the key structure of many drugs (J.Med.Chem.2016,59,8712-8756) and secondary metabolites (Chem.Soc.Rev.2012,41,4631-4642). Due to its good particle stability, metabolic stability and brain permeability, compounds containing cyclopropane structures are widely used in the design of small molecule drugs. In 2019, 9 drugs in the top 200 global drug sales contained cyclopropane structures. Currently, the FDA has approved more than 60 drug molecules containing cyclopropane, including central nervous system (CNS) drugs, cardiovascular drugs, antidiabetic drugs, autoimmune and anti-inflammatory drugs, anticancer drugs, antiviral drugs, antibacterial drugs and respiratory disorder drugs. Therefore, the cyclopropane ring has a wide range of applications in drug molecule design. The introduction of cyclopropyl groups in drugs can change the various properties of the molecules.

[0003] Cyclopropane has a carbon-carbon bond angle of 120°, which is much higher than sp 3 The standard bond angle of the hybrid is 109°28′, so cyclopropane has a higher ring tension and therefore has good chemical reactivity. It is also widely used in synthetic chemistry. Using cyclopropane as a reaction precursor, the synthesis of many complex compounds has been completed (Chin. Chem. Lett., 2022, 33, 4257-4260).

[0004] Generally, the synthesis of cyclopropane compounds is mainly obtained by reacting diazomethane (Org. Lett, 2022, 24, 1637-1641), metal carbenes (Org. Chem. Front., 2018, 5, 1768-1771), p-toluenesulfonylhydrazone compounds (Angew. Chem. Int. Ed., 2016, 55, 1810-1815) with another molecule of double bond compound. These reaction raw materials are generally highly toxic or the reagents are explosive, and their use often requires strict safety precautions. The use of such reagents under extreme conditions is also subject to many restrictions.

[0005] Visible light is a clean, efficient and sustainable energy source. In recent years, with the development of various types of photocatalysts, the types of reactions promoted by visible light have been greatly expanded. Using safe cyclopropane precursors, visible light-promoted cyclopropanation reactions under the action of photocatalysts have been reported: the cyclopropanation reagent is simple to synthesize and the reaction conditions are mild, and cyclopropane compounds without substitution on the methylene group can be obtained.

[0006] Although photochemical reactions have the advantage of being environmentally friendly, the scale of their reactions has always troubled chemists. The photon reception efficiency is extremely low when using conventional solvent bottles and LED lamps. Once the reaction scale is scaled up, the yield is significantly reduced. In addition, the melting point of the commonly used solvent dimethyl sulfoxide is only 18.4°C at normal pressure, so the reaction system is often unusable in scenarios with slightly lower temperatures. Summary of the invention

[0007] The technical problem to be solved by the present invention is to improve the synthesis yield and scale by optimizing the cyclopropanation reagent, reaction mode and reaction system.

[0008] In order to solve the above technical problems, the specific technical solutions adopted by the present invention are as follows:

[0009] A visible light-promoted continuous flow synthesis method for cyclopropane compounds, wherein the cyclopropane compounds are as shown in formula I, and are characterized by comprising the following steps: an olefin compound as shown in formula II, a cyclopropanation agent as shown in formula III, a photocatalyst, and an organic solvent are introduced into a reactor, and the cyclopropane compounds are obtained under the action of light;

[0010]

[0011] Where: R 1 are independently phenyl, 4-fluorophenyl, methyl, hydrogen;

[0012] R 2 are independently trifluoromethyl, ethoxy, or hydrogen;

[0013] R 3 are independently cyano, carbomethoxy, carboethoxy, benzoyl, phenyl, trifluoromethyl, alkoxyphenyl, or hydrogen.

[0014] In some specific embodiments, the photocatalyst is selected from one or more of Ru(bpy)3Cl2, Ru(bpy)з(PF6)2, Ir(ppy)3, Ir(ppy)2(dtbbpy)PF6, Ir[dF(CF3)ppy]2(dtbbpy)PF6, and Ir[dF(CF3)ppy]2[d(CF3)bpy)]PF6.

[0015] Preferably, the photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6, and the structural formula is as follows:

[0016]

[0017] In some specific embodiments, the organic solvent is selected from one or more of methanol, acetonitrile, dimethyl sulfoxide, and N,N-dimethylformamide.

[0018] Preferably, the organic solvent is a mixed solvent of dimethyl sulfoxide and N,N-dimethylformamide in a volume ratio of 0 to 3:1.

[0019] In some specific embodiments, the reactor is a flow reactor, the inner diameter of the pipeline of the flow reactor is 1 / 16 to 1 / 8 inch, and the length of the pipeline is 10 to 15 m.

[0020] Preferably, the inner diameter of the pipeline is 1 / 8 inch and the length of the pipeline is 15m.

[0021] Preferably, the reactor uses a polyperfluoroethylene propylene pipe.

[0022] In some specific embodiments, the illumination uses visible light with a wavelength of 405 to 520 nm.

[0023] A preferred wavelength is visible light at 450 nm.

[0024] In some specific embodiments, the reaction temperature is 0-60°C.

[0025] The preferred reaction temperature is 30°C.

[0026] In some specific embodiments, the reaction time is 10 to 120 minutes.

[0027] The preferred reaction time is 30 min.

[0028] The progress of the reaction can be monitored by conventional monitoring methods in the art, such as thin layer chromatography (TLC), gas chromatography (GC), nuclear magnetic resonance spectroscopy (NMR) or high performance liquid chromatography (HPLC).

[0029] The post-reaction treatment step can be a conventional post-treatment step for this type of reaction in the art, for example, filtration, extraction, column chromatography, and crystallization to obtain the compound of formula I.

[0030] In some specific embodiments, the structural formula of the cyclopropane compound is as follows:

[0031]

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] By optimizing the reaction conditions such as cyclopropanation reagents and solvents and combining the photocatalytic reaction with the continuous flow method, the reaction time is greatly shortened, the reaction has better universality at low temperatures, and the yield and scale of cyclopropane compounds are improved.

[0034] The concept and technical effects of the present invention will be further described below in conjunction with specific implementation methods to fully understand the purpose, characteristics and effects of the present invention. DETAILED DESCRIPTION

[0035] In order to make the technical means, creative features, objectives and effects of the invention easier to understand, the present invention is further described below in conjunction with the embodiments. However, the present invention is not limited to the following implementation cases.

[0036] It should be noted that this specification is intended for people familiar with this technology to understand and read, and is not intended to limit the conditions under which the present invention can be implemented. Therefore, it has no substantive technical significance and no creative adjustments. Without affecting the effects and purposes that can be achieved by the present invention, it should still fall within the scope of the technical content disclosed by the present invention.

[0037] All reagents involved in the examples are commercially available products and can be commercial products.

[0038] A preferred visible light-promoted continuous flow synthesis method for cyclopropane compounds is as follows:

[0039]

[0040] A 100 mL round-bottom flask was added with a magnetic bar, and after baking in an oven at 150° C. for half an hour, dry nitrogen was passed through the flask until it returned to room temperature. Olefin compound II (1 mmol), photocatalyst IV (2 mol%): bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium(hexafluorophosphate) salt [Ir(dFCF3ppy)2(dtbbpy)]PF6 (CAS: 870987-63-6), cyclopropane reagent III (1.5 eq): hydrogen-2-(iodomethyl)-2,2-spiro[[1,3,2]benzodioxasilyl]-2-salt triethylamine salt (CAS: 2230030-49-4), dimethyl sulfoxide 5 mL, N,N-dimethylformamide 5 mL, and nitrogen was passed through the flask for 30 minutes to deoxygenate. The reaction solution was pumped into the reaction device using a peristaltic pump, and the flow rate of the solution was calibrated to be 0.25 mL / min. The reaction device contained a 30 mL polyperfluoroethylene propylene pipe with an inner diameter of 1 / 8 inch; a LED lamp with a wavelength of 450 nm and an energy consumption of 400 W; and a heater in the device with a constant temperature of 30 ° C. After 40 minutes, when the pumping of the solution in the reaction bottle was completed, 10 mL of dimethyl sulfoxide and 10 mL of N, N-dimethylformamide were added and continued to be pumped into the reaction device for cleaning the container and pipes. After 120 minutes, a 100 mL round-bottom flask was used to collect the outflowing reaction solution. After 160 minutes, the reaction solution was stopped, 30 mL of saturated sodium carbonate solution was added, and then 3×30 mL of ethyl acetate was added for extraction. The solvent was dried using a rotary evaporator, dibromomethane was used as the internal standard, and deuterated chloroform was used as the solvent. The product structure and yield were confirmed by nuclear magnetic resonance characterization.

[0041] The synthesis methods of the following specific examples refer to the above method.

[0042] Example 1

[0043] Formula I is

[0044] That is, the product is 1,1-diphenylcyclopropane (cyclopropane-1,1-diyldibenzene), and the NMR yield is 95%.

[0045] NMR analysis data: 1 H-NMR (CDCl3, 400MHz) δ7.31-7.23 (m, 8H), 7.19 (m, 2H), 1.32 (s, 4H).

[0046] Example 2

[0047] Formula I is

[0048] That is, 1-(trifluoromethyl)cyclopropylbenzene (1-(trifluoromethyl)cyclopropyl)benzene), with a NMR yield of 85%.

[0049] NMR analysis data: 1 H-NMR (CDCl3, 400MHz) δ7.53-7.33(m,5H),1.38-1.33(m,2H),1.00(s,2H).

[0050] Example 3

[0051] Formula I is

[0052] That is, ethyl 1-phenylcyclopropane-1-carboxylate, with a NMR yield of 80%.

[0053] NMR analysis data: 1 H-NMR (CDCl3, 400MHz) δ7.39-7.35 (m, 4H), 7.28-7.24 (m, 1H), 4.10 (q, J = 7.1Hz, 2H ), 1.60 (dd, J = 7.1, 3.6 Hz, 2H), 1.19 ( dd, J = 6.8, 3.6 Hz, 2H), 1.17 ( t, J = 6.8 Hz, 3H).

[0054] Example 4

[0055] Formula I is

[0056] That is, 1-methoxy-4-((1S,2S)-2-methylcyclopropyl)benzene (1-methoxy-4-((1S,2S)-2-methylcyclopropyl)benzene), with an NMR yield of 53%.

[0057] NMR analysis data: 1 H-NMR(CDCl3,400MHz)δ7.99(d,J=8.8Hz,2H),6.95(d,J=8.8Hz,2H),3.87(s,3H),2.34(dt,J=8.0,4 .2Hz,1H),1.62-1.52(m,1H),1.45(dt,J=8.4,4.0Hz,1H),1.21(d,J=6.1Hz,3H),0.81-0.87(m,1H).

[0058] Example 5

[0059] Formula I is

[0060] That is, methyl (1S, 2S)-2-phenylcyclopropane-1-carboxylate, with an NMR yield of 71%.

[0061] NMR analysis data: 1 H-NMR(CDCl3,400MHz)δ7.29(t,J=7.6Hz,1H),7.21(tt,J=7.6,1.6Hz,1H),7.11(d,J=6.8Hz,2H),3.73(s,3H),2.54(ddd, J=9.2,6.4,4.0Hz,1H),1.92(ddd,J=8.4,5.2,4.0Hz,1H),1.62(dt,J=9.2,4.8Hz,1H),1.33(ddd,J=8.4,6.4,4.8Hz,1H).

[0062] Example 6

[0063] Formula I is

[0064] That is, ethyl (1S, 2S)-2-phenylcyclopropane-1-carboxylate, with a NMR yield of 77%.

[0065] NMR analysis data: 1 H-NMR(CDCl3,400MHz)δ7.29(t,J=7.6Hz,2H),7.21(t,J=7.6Hz,1H),7.11(d,J=7.2Hz,2H),4.18(q,J=7.2Hz,2H),2 .49-2.56(m,1H),1.91(dt,J=9.2,4.8Hz,1H),1.61(dt,J=9.2,4.8Hz,1H),1.30-1.34(m,1H),1.29(t,J=7.2Hz,3H).

[0066] Example 7

[0067] Formula I is

[0068] That is, methyl (1S, 2S)-2-(4-fluorophenyl) cyclopropanecarboxylate (methyl (1S, 2S)-2-(4-fluorophenyl) cyclopropane-1-carboxylate), with an NMR yield of 75%.

[0069] NMR analysis data: 1H-NMR (CDCl3, 400MHz) δ7.29 (m, 2H), 7.11 (m, 2H), 4.18 (q, J = 7.2Hz, 2H), 2.49-2.56 (m, 1H), 1.9 1(dt,J=9.2,4.8Hz,1H),1.61(dt,J=9.2,4.8Hz,1H),1.30-1.34(m,1H),1.29(t,J=7.2Hz,3H).

[0070] Example 8

[0071] Formula I is

[0072] That is, phenyl((1S,2S)-2-phenylcyclopropane-1-yl)methanone (phenyl((1S,2S)-2-phenylcyclopropyl)methanone), with an NMR yield of 61%.

[0073] NMR analysis data: 1 H-NMR(CDCl3,400MHz)δ8.00(d,J=7.2Hz,2H),7.56(t,J=6.8Hz,1H),7.46(t,J=7.6Hz,2H),7.32(t,J=7.6Hz,2H),7.23(t,J=7.2Hz,1H ),7.19(d,J=7.2Hz,2H),2.91(dt,J=9.2,4.4Hz,1H),2.62-2.75(m,1H),1.93(dt,J=9.2,4.8Hz,1H),1.56(ddd,J=7.6,6.8,4.0Hz,1H).

[0074] The synthetic method adopted in the following comparative examples is as follows:

[0075] A 100 mL round-bottom flask was added with a magnetic bar, and after baking in an oven at 150° C. for half an hour, dry nitrogen was passed through to restore to room temperature, and ethyl cinnamate (103-36-6) (1 mmol), photocatalyst IV (2 mol%): bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium(hexafluorophosphate) salt [Ir(dFCF3ppy)2(dtbbpy)]PF6 (CAS: 870987-63-6), cyclopropane reagent III (1.5 eq): hydrogen-2-(iodomethyl)-2,2-spiro[[1,3,2]benzodioxasilyl]-2-salt triethylamine salt (CAS: 2230030-49-4), solvent was added, and nitrogen was passed through for 30 minutes to deoxygenate. The reaction solution was pumped into the reaction device using a peristaltic pump, and the flow rate of the solution was calibrated to 0.25 mL / min. The reaction device contained a 30 mL polyperfluoroethylene propylene pipe with an inner diameter of 1 / 8 inch; a LED lamp with a wavelength of 450 nm and an energy consumption of 400 W; and a heater in the device with a constant temperature of 30 ° C. After 40 minutes, the pumping of the solution in the reaction bottle was completed, and another 20 mL of solvent was added and continued to be pumped into the reaction device for cleaning the container and pipes. After 120 minutes, a 100 mL round-bottom flask was used to collect the outflowing reaction solution. After 150 minutes, the reaction solution was stopped, 30 mL of saturated sodium carbonate solution was added, and then 3×30 mL of ethyl acetate was added for extraction. The solvent was dried using a rotary evaporator, dibromomethane was used as an internal standard, and deuterated chloroform was used as a solvent. The product structure and yield were confirmed by nuclear magnetic resonance characterization.

[0076] Comparative Example 1

[0077] Formula I is

[0078] That is, ethyl (1S, 2S)-2-phenylcyclopropanecarboxylate (ethyl (1S, 2S)-2-phenylcyclopropane-1-carboxylate).

[0079] The selected solvent is dimethyl sulfoxide, and the reaction temperature is changed to 30°C. If the room temperature is less than 10°C, the use of this solvent will cause ice to form in the reactor, hindering the reaction. Therefore, the reaction cannot proceed smoothly.

[0080] Comparative Example 2

[0081] Formula I is the same as Comparative Example 1.

[0082] The selected solvent is N,N-dimethylformamide. The NMR yield is 70%.

[0083] Comparative Example 3

[0084] Formula I is the same as Comparative Example 1.

[0085] The selected solvent is a mixed solvent of N,N-dimethylformamide and dimethyl sulfoxide, with a volume ratio of 3:1. The NMR yield is 70%.

[0086] Comparative Example 4

[0087] Formula I is the same as Comparative Example 1.

[0088] The selected solvent is a mixed solvent of N,N-dimethylformamide and dimethyl sulfoxide, with a volume ratio of 1:3. The NMR yield is 74%.

[0089] Comparative Example 5

[0090] Formula I is the same as Comparative Example 1.

[0091] The selected solvent is a mixed solvent of acetonitrile and dimethyl sulfoxide, with a volume ratio of 1:1. The NMR yield is 60%.

[0092] Comparative Example 6

[0093] Formula I is the same as Comparative Example 1.

[0094] The selected solvent is a mixed solvent of methanol and dimethyl sulfoxide, with a volume ratio of 1:1. The NMR yield is 55%.

[0095] From the above examples and comparative examples, it can be seen that the cyclopropanation reagent used in the present invention can obtain cyclopropane compounds with a high yield. It is found through experiments that N, N-dimethylformamide or a mixed solvent of N, N-dimethylformamide and dimethyl sulfoxide can significantly increase the yield of cyclopropane compounds. At the same time, the synthesis method of the present invention can multiply the reaction scale.

[0096] The preferred specific embodiments of the present invention are described in detail above. It should be understood that ordinary technicians in the field can make many modifications and changes based on the concept of the present invention without creative work. Therefore, all technical solutions that can be obtained by technicians in the technical field based on the concept of the present invention through logical analysis, reasoning or limited experiments on the basis of the prior art should be within the scope of protection determined by the claims.

Claims

1. A visible light-promoted continuous flow synthesis method for cyclopropane compounds, wherein the cyclopropane compounds are as shown in formula I, characterized in that: The method comprises the following steps: an olefin compound as shown in formula II, a cyclopropanation agent as shown in formula III, a photocatalyst, and an organic solvent are introduced into a reactor, and a cyclopropane compound is obtained under the action of light; Where: R 1 are independently phenyl, 4-fluorophenyl, methyl, hydrogen; R 2 are independently trifluoromethyl, ethoxy, or hydrogen; R 3 are independently cyano, carbomethoxy, carboethoxy, benzoyl, phenyl, trifluoromethyl, alkoxyphenyl, or hydrogen.

2. The synthesis method according to claim 1, characterized in that The photocatalyst is selected from one or more of Ru(bpy)3Cl2, Ru(bpy)з(PF6)2, Ir(ppy)3, Ir(ppy)2(dtbbpy)PF6, Ir[dF(CF3)ppy]2(dtbbpy)PF6, and Ir[dF(CF3)ppy]2[dtbbpy)]PF6.

3. The synthesis method according to claim 2, characterized in that The photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6, and the structural formula is as follows:

4. The synthesis method according to claim 1, characterized in that The organic solvent is selected from one or more of methanol, acetonitrile, dimethyl sulfoxide, and N,N-dimethylformamide.

5. The synthesis method according to claim 4, characterized in that The organic solvent is a mixed solvent of dimethyl sulfoxide and N,N-dimethylformamide, with a volume ratio of 0 to 3:

1.

6. The synthesis method according to claim 1, characterized in that The reactor is a flow reactor, the inner diameter of the pipeline of the flow reactor is 1 / 16 to 1 / 8 inch, and the length of the pipeline is 10 to 15 meters.

7. The synthesis method according to claim 1, characterized in that The illumination adopts visible light with a wavelength of 450nm.

8. The synthesis method according to claim 1, characterized in that The reaction temperature was 30°C.

9. The synthesis method according to claim 1, characterized in that The reaction time is 30 minutes.

10. The synthesis method according to claim 1, characterized in that The structural formula of the cyclopropane compound is as follows:

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