A flow chemistry method for reducing carboxylic acids to alcohols with diisobutylaluminum hydride

Abstract

The application discloses a flow chemistry method for reducing carboxylic acid to alcohol by diisobutylaluminum hydride, which comprises the following steps: S1, dissolving a reaction substrate containing a carboxyl group in a first solvent to prepare solution A; S2, dissolving diisobutylaluminum hydride in a second solvent to prepare solution B; and S3, pumping solution A and solution B into a coil through a pump respectively, quenching the reaction liquid after the reaction is completed, and obtaining a target product. The flow chemistry method for reducing carboxylic acid to alcohol by diisobutylaluminum hydride has mild reaction conditions, reduces the reaction risk, avoids the risk of material flushing, and realizes stable operation.

Description

Technical Field

[0001] This invention relates to the field of flow chemistry, and more particularly to a flow chemistry method for reducing carboxylic acids to alcohols using diisobutylaluminum hydride as a reducing agent. Background Technology

[0002] Common reducing agents for reducing carboxylic acids to alcohols include LiAlH4, NaBH4 / activator, and BH3. LiAlH4 has strong reducing power but poor substrate functional group compatibility; during the reduction of carboxylic acids to alcohols, substrate functional groups such as nitro, halogen, nitrile, and ester groups will be affected. NaBH4 cannot directly reduce carboxylic acids and requires the addition of an activator. Common activators include I2, Lewis acids (BF3·Et2O, TiCl4, ZnCl2, CaCl2, ZrCl4, etc.) or protic acids (H2SO4, MsOH, HCl). For example, application number 201310068886.9 discloses a method for synthesizing 2-chloro-5-trifluoromethylbenzyl alcohol, using 2-chloro-5-trifluoromethylbenzoic acid as a raw material and selecting sodium borohydride and boron trifluoride as reducing agents to prepare 2-chloro-5-trifluoromethylbenzyl alcohol, where boron trifluoride is the activator. LiBH4 and Zn(BH) 4)2 It can also be used for the reduction of acids. The reaction of LiBH4 generally requires the addition of an activator, the most common of which is TMSCl. In addition, borane (BH3·Me2S or BH3·THF), red aluminum (NaAlH2(OCH2CH2OMe)2), and DIBAL-H (diisobutylaluminum hydride) can also reduce carboxylic acids to primary alcohols.

[0003] The process of reducing carboxylic acids to alcohols with the above-mentioned reducing agents is mostly carried out in traditional batch reactors. This process has problems such as untimely heat exchange and the risk of material overflow due to heat accumulation. Moreover, the reducing agents have strong reducing properties and poor compatibility with functional groups, requiring strict temperature control. Otherwise, there will be more by-products and complicated post-processing. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention provides a flow chemistry method for reducing carboxylic acids to alcohols using diisobutylaluminum hydride. The reaction substrate and the reducing agent diisobutylaluminum hydride are introduced into a coil at a certain flow rate. Diisobutylaluminum hydride can reduce carboxylic acids to alcohols without affecting other substituents in the reaction substrate. Furthermore, the reaction conditions are mild, there is no risk of material overflow, and the post-processing is simple.

[0005] To address the above problems, this invention provides a flow chemistry method for reducing carboxylic acids to alcohols using diisobutylaluminum hydride, comprising the following steps:

[0006] S1. Dissolve the carboxyl-containing reaction substrate in the first solvent to prepare solution A;

[0007] S2. Dissolve diisobutylaluminum hydride in the second solvent to prepare solution B;

[0008] S3. Pump solutions A and B into the coil respectively using a pump. After the reaction is complete, quench the reaction solution to obtain the target product.

[0009] In a preferred embodiment, the first solvent is selected from any one of tetrahydrofuran, dichloromethane, and toluene.

[0010] In a preferred embodiment, the second solvent is selected from toluene or hexane.

[0011] In a preferred embodiment, when the amount of the reaction substrate is 1 molar equivalent, the amount of diisobutylaluminum hydride is 3-5 molar equivalents.

[0012] In a preferred embodiment, the reaction temperature in S3 is 0-30°C.

[0013] In a preferred embodiment, the reaction temperature in S3 is 10-30°C.

[0014] In a preferred embodiment, the reaction temperature in S3 is 10-20°C.

[0015] In a more preferred embodiment, the reaction temperature in S3 is 15-20°C.

[0016] In a preferred embodiment, the reaction time in S3 is 10-120 minutes.

[0017] In a more preferred embodiment, the reaction time in S3 is 10-15 minutes.

[0018] The lower the reaction temperature, the longer the reaction time. At 0℃, it takes nearly 120 minutes for the reaction to complete. Based on repeated comparative experiments, when the reaction temperature is close to 15-20℃, the reaction can be completed in 10-15 minutes. As the reaction temperature continues to rise, the reaction time shortens further. At this point, the influence of gases on the reaction becomes significant, even affecting the stability of the reaction. Therefore, 15-20℃ is selected as the optimal reaction temperature.

[0019] In S3, the reaction temperature is controlled at 15-20℃ and the reaction time is 10-15 minutes, which allows for a complete reaction. The reaction occurs at near room temperature, the reaction conditions are mild, and the reaction time is short, which improves work efficiency.

[0020] As a preferred embodiment, the general formula of the carboxyl-containing reaction substrate is as follows:

[0021]

[0022] R1 is selected from one or more of -H, -Br, -Cl, -F, -NH2, -CF3, -CH3, -I, -OMe, -CH2Br, -NO2, and -OH.

[0023] As a more preferred embodiment, the general formula of the reaction substrate containing a carboxyl group is as follows:

[0024]

[0025] Where A is selected from any one of -F, -Cl, -Br, -I, -H, -NH2, -CF3, -NO2, -OH, -CH3, -OMe;

[0026] B is selected from any one of -F, -Cl, -Br, -I, -H, -OMe, -CF3, -CH2Br, -NO2, -OH, -CH3;

[0027] C is selected from any one of -F, -Cl, -Br, -I, -H, -CF3, -CH3, -CH2Br, -NO2, -OH;

[0028] E is selected from any one of -F, -Cl, -Br, -I, -H, -CH3, -CF3, -OMe, -NO2, -OH;

[0029] F is selected from any one of -F, -Cl, -Br, -I, -H, -CH3, -OMe, -NO2, -NH2, -CF3.

[0030] In a more preferred embodiment, A is selected from any one of -F, -Cl, -Br, -I, -H, -CH3, -NH2, -OMe, -NO2, -CF3;

[0031] B is selected from any one of -F, -Cl, -Br, -I, -H, -OMe, -CF3, -NO2, -CH3;

[0032] C is selected from any one of -F, -Cl, -Br, -I, -H, -CF3, -CH3, -CH2Br, -NO2, -OH;

[0033] E is selected from any one of -F, -Cl, -Br, -I, -H, -CF3, -CH3, -NO2, -OH, -OMe;

[0034] F is selected from any one of -F, -Cl, -Br, -I, -H, -CH3, -NH2, -OMe, -NO2, -CF3.

[0035] In a more preferred embodiment, A is selected from any one of -F, -Cl, -Br, -I, -H, -CH3, -NH2, -OMe, -NO2;

[0036] B is selected from any one of -F, -Cl, -Br, -I, -H, -OMe, -CF3, -NO2, -CH3;

[0037] C is selected from any one of -F, -Br, -H, -CF3, -CH3, -CH2Br, -NO2;

[0038] E is selected from any one of -I, -H, -CH3, -Br, -OMe, -Cl, -NO2, -OH;

[0039] F is selected from any one of -F, -Cl, -H, -CH3, -Br, -I, -OMe, -NO2, -NH2.

[0040] In a more preferred embodiment, A is selected from -H;

[0041] B is selected from any one of -H, -Br, -I, -Cl, -F, -CF3, -OMe, -NO2;

[0042] C is selected from any one of -Br, -H, -F, -CF3, -CH3, -CH2Br, -NO2;

[0043] E is selected from any one of -CH3, -I, -H, -OMe, -Br, -NO2;

[0044] F is selected from any one of -H, -Cl, -CH3, -Br, -I, -NO2, -NH2.

[0045] In a more preferred embodiment, A is selected from any one of -F, -I, -Br, and -Cl;

[0046] B is selected from any one of -H, -OMe, and -NO2;

[0047] C is selected from -Br or -H;

[0048] E is selected from -H or -Cl;

[0049] F is selected from any one of -F, -H, -CH3, and -OMe.

[0050] As a more preferred embodiment, wherein

[0051] A is selected from -NH2;

[0052] B is selected from -H or -CH3;

[0053] C is selected from -F or -H;

[0054] E is selected from -Br or -H;

[0055] F is selected from -H or -Cl.

[0056] As a more preferred embodiment, wherein

[0057] A is selected from -CH3;

[0058] B is selected from -Br or -NO2;

[0059] C is selected from -H;

[0060] E is selected from -H or -Cl;

[0061] F is selected from -H.

[0062] As a more preferred embodiment, the reaction substrate containing a carboxyl group is:

[0063]

[0064] As a preferred embodiment, the general formula of the carboxyl-containing reaction substrate is as follows:

[0065]

[0066] R2 is selected from one or more of -H, -Br, -Cl, -F, -NH2, -CF3, -CH3, -I, -OMe, -CH2Br, -NO2, and -OH.

[0067] As a more preferred embodiment, the general formula of the reaction substrate containing a carboxyl group is as follows:

[0068]

[0069] Wherein G is selected from any one of -F, -Cl, -Br, -I, -H, -NH2, -CF3, -NO2, -OH, -CH3, -OMe;

[0070] H is selected from any one of -F, -Cl, -Br, -I, -H, -OMe, -CF3, -CH2Br, -NO2, -OH, -CH3;

[0071] I is selected from any one of -F, -Cl, -Br, -I, -H, -CF3, -CH3, -CH2Br, -NO2, -OH;

[0072] J is selected from any one of -F, -Cl, -Br, -I, -H, -CH3, -OMe, -NO2, -NH2, -CF3.

[0073] As a more preferred embodiment, wherein

[0074] G is selected from -H;

[0075] H is selected from any one of -F, -Cl, -Br, -I, and -H;

[0076] I is selected from any one of -F, -Cl, -Br, -I, -H, -CF3, -CH3;

[0077] J is selected from any one of -F, -Cl, -Br, -I, -H, -CF3.

[0078] As a more preferred embodiment, the reaction substrate containing a carboxyl group is:

[0079]

[0080] As a more preferred embodiment, the reaction substrate containing a carboxyl group is:

[0081]

[0082] In a more preferred embodiment, the method further includes

[0083] S4. Add ethyl acetate to the quenched reaction solution for extraction;

[0084] S5. Add anhydrous sodium sulfate, dry, and then concentrate.

[0085] In a preferred embodiment, the flow rate of solution A in the coil is 0.38-5 mL / min.

[0086] The flow rate of solution B in the coil is controlled based on the flow rate of solution A and the molar equivalent ratio between the substrate and the reducing agent.

[0087] Compared with the prior art, the present invention has the following beneficial effects:

[0088] (1) The present invention uses a flow chemistry method for reducing carboxylic acids to alcohols with diisobutylaluminum hydride. The reaction conditions are mild, which reduces the risk of reaction, avoids the risk of material spillage, and achieves stable operation.

[0089] (2) The present invention uses a flow chemistry method for reducing carboxylic acids to alcohols with diisobutylaluminum hydride, which overcomes the problem of poor compatibility of reducing agents with functional groups of reaction substrates, and the post-processing is simple, avoiding cumbersome post-processing steps.

[0090] (3) The present invention uses a flow chemistry method to reduce carboxylic acids to alcohols with diisobutylaluminum hydride. The reaction time is short, and the reaction can be completed in about 10 minutes, which improves the efficiency of work.

[0091] The following will further explain the concept, specific structure, and technical effects of the present invention in conjunction with the accompanying drawings, so as to fully understand the purpose, features, and effects of the present invention. Attached Figure Description

[0092] Figure 1 This is a schematic diagram of the flow chemistry method of reducing carboxylic acids to alcohols using diisobutylaluminum hydride according to the present invention.

[0093] Wherein: 1-pump, 2-coil. Detailed Implementation

[0094] To make the technical means, inventive features, objectives, and effects of the invention readily understandable, the invention is further illustrated below with reference to specific figures. However, the invention is not limited to the embodiments described below.

[0095] The term "embodiment" used herein, as an example, is not necessarily to be construed as superior to or better than other embodiments. Performance tests in these embodiments of the invention, unless otherwise specified, employ conventional testing methods in the art. It should be understood that the terminology used herein is merely for describing particular implementations and is not intended to limit the scope of the disclosure.

[0096] Unless otherwise stated, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains; other experimental methods and techniques not specifically mentioned herein refer to experimental methods and techniques commonly used by one of ordinary skill in the art.

[0097] Numerical data presented in range format in this document are for convenience and brevity only, and should therefore be interpreted flexibly to include not only the explicitly listed values ​​that define the range's boundaries, but also all independent values ​​or subranges contained within that range. For example, the numerical range "1–5%" should be interpreted to include not only the explicitly listed values ​​from 1% to 5%, but also independent values ​​and subranges within the indicated range. Thus, this numerical range includes independent values ​​such as 2%, 3.5%, and 4%, and subranges such as 1%–3%, 2%–4%, and 3%–5%, etc. This principle also applies to ranges that list only one value. Furthermore, this interpretation applies regardless of the width of the range or its characteristics.

[0098] To better illustrate the content of this invention, numerous specific details are provided in the following detailed embodiments. Those skilled in the art should understand that the invention can be implemented even without certain specific details. In the embodiments, some methods, means, instruments, and devices well-known to those skilled in the art are not described in detail, in order to highlight the main points of the invention. Without conflict, the technical features disclosed in the embodiments of this invention can be arbitrarily combined, and the resulting technical solutions belong to the content disclosed in the embodiments of this invention.

[0099] Common reducing agents for reducing carboxylic acids to alcohols include LiAlH4, NaBH4 / activator, and BH3. LiAlH4 has strong reducing power but poor substrate functional group compatibility; NaBH4 requires other activators; and BH3 has a fast reaction rate, requiring strict control of the amount of borane and the reaction temperature to avoid affecting the substrate functional groups. Furthermore, current methods for reducing carboxylic acids to alcohols using these reducing agents all employ traditional batch reactors, which suffer from slow heat exchange and a risk of backflow. The inventors of this application propose using a fluid chemistry approach to address these issues. By selecting a suitable reducing agent and allowing the reaction to occur under mild conditions, the poor substrate functional group compatibility can be resolved while avoiding the risk of backflow.

[0100] Fluid chemistry, also known as flow chemistry, refers to chemical reactions that occur in continuously flowing systems. Due to its numerous advantages, fluid chemistry is widely used in various fields. However, in the reaction process of this invention, repeated reactions under the same conditions may yield significantly different results, raising questions about stability. Through repeated exploration and experimentation, the inventors discovered that the fundamental reason affecting reaction stability and reaction time lies in the generated gas.

[0101] This invention generates gas during the reaction process. In traditional batch reactors, due to the large space of the reactor, the driving effect of the gas on the reaction liquid is not significant, and the effect of the gas is negligible. However, when using flow chemical reactions, the driving effect of the gas cannot be ignored, and may even affect the stability and reaction time of the reaction.

[0102] To address this problem, the inventors adopted two approaches. The first approach involves extending the residence time, from the original 3 minutes to approximately 10 minutes, such as by reducing the flow rate or increasing the total length of the coil. The second approach involves adjusting the T-tube at the three-way valve to a three-necked flask, and simultaneously installing another pump at the rear end of coil 2 to extract the reaction substrate and reducing agent from the three-necked flask into coil 2 to participate in the reaction. At the same time, the gas generated in coil 2 is also extracted, overcoming the influence of gas on the entire reaction process, thereby increasing the stability of the reaction and effectively reducing the reaction time.

[0103] like Figure 1 A flow chemistry method for reducing carboxylic acids to alcohols using diisobutylaluminum hydride includes the following steps:

[0104] S1. Dissolve the carboxyl-containing reaction substrate in the first solvent to prepare solution A;

[0105] S2. Dissolve diisobutylaluminum hydride in the second solvent to prepare solution B;

[0106] S3. Pump solutions A and B into coil 2 using pump 1. After the reaction is complete, quench the reaction solution to obtain the target product.

[0107] Pump 1 can be either a peristaltic pump or a plunger pump.

[0108] The choice of quencher determines the complexity of the post-processing steps; an improper choice of quencher can easily lead to the formation of gel-like complexes. The inventors of this application attempted to quench the reaction solution by pouring it into a saturated sodium potassium tartrate solution. In this case, the quencher is a saturated sodium potassium tartrate solution, which reduces the likelihood of producing gel-like solids. If gel-like solids do appear, it will make it difficult to separate the layers during extraction. Depending on the system conditions, acid or alkali can be added to make the system easier to separate into layers.

[0109] To minimize the risk of forming a gel-like solid, after the reaction was complete, water was added dropwise to the reaction solution, followed by NaOH solution, and finally water was added again. This quenched the diisobutylaluminum hydride into a sand-like solid, which was then filtered off. Assume that the mass of the diisobutylaluminum hydride in the experiment was X g, the mass of water added in the first step was 0.04X g, the mass of water added in the second step was 0.1X g, and the mass of NaOH solution added was 0.04X g, with a mass fraction of 15%.

[0110] Of course, to make the quenching step simple and efficient, a 1 mol / L NaOH aqueous solution can be used to quench the reaction solution, and the final product can also be obtained through subsequent processing steps.

[0111] The general reaction formula for a reaction substrate containing a carboxyl group is:

[0112]

[0113] R1 is selected from one or more of -H, -Br, -Cl, -F, -NH2, -CF3, -CH3, -I, -OMe, -CH2Br, -NO2, and -OH.

[0114] In addition to the carboxyl group, the substrate contains other functional groups. The method of this invention can reduce carboxylic acids to alcohols without affecting other functional groups, thus exhibiting good selectivity.

[0115] As a more preferred embodiment, the general formula of the reaction substrate containing a carboxyl group is as follows:

[0116]

[0117] Where A is selected from any one of -F, -Cl, -Br, -I, -H, -NH2, -CF3, -NO2, -OH, -CH3, -OMe; B is selected from any one of -F, -Cl, -Br, -I, -H, -OMe, -CF3, -CH2Br, -NO2, -OH, -CH3; C is selected from any one of -F, -Cl, -Br, -I, -H, -CF3, -CH3, -CH2Br, -NO2, -OH; E is selected from any one of -F, -Cl, -Br, -I, -H, -CH3, -CF3, -OMe, -NO2, -OH; and F is selected from any one of -F, -Cl, -Br, -I, -H, -CH3, -OMe, -NO2, -NH2, -CF3.

[0118] In a more preferred embodiment, A is selected from -F, -Cl, -Br, -I, -H, -CH3, -NH2, -OMe, -NO 2, B is selected from any one of -CF3; B is selected from any one of -F, -Cl, -Br, -I, -H, -OMe, -CF3, -NO2, -CH3; C is selected from any one of -F, -Cl, -Br, -I, -H, -CF3, -CH3, -CH2Br, -NO2, -OH; E is selected from any one of -F, -Cl, -Br, -I, -H, -CF3, -CH3, -NO2, -OH, -OMe; F is selected from any one of -F, -Cl, -Br, -I, -H, -CH3, -NH2, -OMe, -NO2, -CF3.

[0119] In a more preferred embodiment, A is selected from any one of -F, -Cl, -Br, -I, -H, -CH3, -NH2, -OMe, -NO2; B is selected from any one of -F, -Cl, -Br, -I, -H, -OMe, -CF3, -NO2, -CH3; C is selected from any one of -F, -Br, -H, -CF3, -CH3, -CH2Br, -NO2; E is selected from any one of -I, -H, -CH3, -Br, -OMe, -Cl, -NO2, -OH; and F is selected from any one of -F, -Cl, -H, -CH3, -Br, -I, -OMe, -NO2, -NH2.

[0120] In a more preferred embodiment, A is selected from -H; B is selected from any one of -H, -Br, -I, -Cl, -F, -CF3, -OMe, -NO2; C is selected from any one of -Br, -H, -F, -CF3, -CH3, -CH2Br, -NO2; E is selected from any one of -CH3, -I, -H, -OMe, -Br, -NO2; and F is selected from any one of -H, -Cl, -CH3, -Br, -I, -NO2, -NH2.

[0121] In a more preferred embodiment, A is selected from any one of -F, -I, -Br, -Cl; B is selected from any one of -H, -OMe, -NO2; C is selected from -Br or -H; E is selected from -H or -Cl; and F is selected from any one of -F, -H, -CH3, -OMe.

[0122] In a more preferred embodiment, A is selected from -NH2; B is selected from -H or -CH3; C is selected from -F or -H; E is selected from -Br or -H; and F is selected from -H or -Cl.

[0123] In a more preferred embodiment, A is selected from -CH3; B is selected from -Br or -NO2; C is selected from -H; E is selected from -H or -Cl; and F is selected from -H.

[0124] As a more preferred embodiment, the reaction substrate containing a carboxyl group is:

[0125]

[0126]

[0127] As a preferred embodiment, the general formula of the carboxyl-containing reaction substrate is as follows:

[0128]

[0129] R2 is selected from one or more of -H, -Br, -Cl, -F, -NH2, -CF3, -CH3, -I, -OMe, -CH2Br, -NO2, and -OH.

[0130] As a more preferred embodiment, the general formula of the reaction substrate containing a carboxyl group is as follows:

[0131]

[0132] Wherein G is selected from any one of -F, -Cl, -Br, -I, -H, -NH2, -CF3, -NO2, -OH, -CH3, -OMe; H is selected from any one of -F, -Cl, -Br, -I, -H, -OMe, -CF3, -CH2Br, -NO2, -OH, -CH3; I is selected from any one of -F, -Cl, -Br, -I, -H, -CF3, -CH3, -CH2Br, -NO2, -OH; J is selected from any one of -F, -Cl, -Br, -I, -H, -CH3, -OMe, -NO2, -NH2, -CF3.

[0133] In a more preferred embodiment, G is selected from -H; H is selected from any one of -F, -Cl, -Br, -I, -H; I is selected from any one of -F, -Cl, -Br, -I, -H, -CF3, -CH3; and J is selected from any one of -F, -Cl, -Br, -I, -H, -CF3.

[0134] As a more preferred embodiment, the reaction substrate containing a carboxyl group is:

[0135]

[0136]

[0137] As a more preferred embodiment, the reaction substrate containing a carboxyl group is:

[0138]

[0139] The first solvent is selected from tetrahydrofuran, dichloromethane, and toluene. However, the choice of the first solvent is not limited to these; any solvent in the prior art capable of dissolving the reaction substrate in this invention can be used as the first solvent.

[0140] The second solvent is selected from toluene or hexane. The second solvent is used to dissolve diisobutylaluminum hydride; any solvent in the prior art capable of dissolving diisobutylaluminum hydride can be used as the second solvent.

[0141] When the amount of the reaction substrate is 1 molar equivalent, the amount of diisobutylaluminum hydride is 3-5 molar equivalents. A sufficient excess of diisobutylaluminum hydride is used to ensure complete reaction of the reaction substrate, avoiding side reactions and subsequent cumbersome processing steps.

[0142] In S3, the reaction temperature is 0-30℃. Diisobutylaluminum hydride (DIBAL-H) ​​is a typical temperature-controlled reducing agent, whose reducing power is affected by the reaction temperature. By controlling the reaction temperature, chemoselectivity and regioselectivity of the reduction reaction can be achieved, but it is usually used at -78℃ to -70℃, which are relatively harsh conditions. The inventors of this application have creatively introduced DIBAL-H into a flow reaction, which can reduce carboxylic acids to alcohols at a temperature of 0-30℃ without affecting the functional groups of the substrate.

[0143] The reaction time in S3 is 3-20 minutes. This short reaction time reduces reaction costs and the manpower required for monitoring the reaction.

[0144] In a more preferred embodiment, the method further includes

[0145] S4. Add ethyl acetate to the quenched reaction solution for extraction;

[0146] S5. Add anhydrous sodium sulfate, dry, and then concentrate.

[0147] The post-processing steps only include extraction, drying, and concentration, making the post-processing simple.

[0148] Coil 2 is a PFA coil.

[0149] Example 1

[0150] Under nitrogen protection, 3 g of substrate 1 (2-chloro-3-nitrobenzoic acid) was dissolved in 30 mL of tetrahydrofuran to prepare solution A (substrate 1, 14.9 mmol, 1 eq); 60 mL of DIBAL (1 mol / L toluene solution, 3.5 eq) was prepared as solution B. DIBAL-H was fed into coil 2 via pump B at a flow rate of 2 mL / min. When DIBAL-H reached point M1, pump A was turned on to push solution A into the coil at a flow rate of 1 mL / min. After approximately 10 min, the reaction solution flowed out of the coil and was quenched with 1 mol / L NaOH aqueous solution. After complete quenching, the reaction solution was extracted with ethyl acetate (50 mL), and the aqueous phase was washed with ethyl acetate (80 mL * 3). All organic phases were pooled together, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2.27 g of product, with a yield of 75%.

[0151] 1 H NMR (400MHz, DMSO-d6) δ = 7.91 (d, J = 8.0Hz, 1H), 7.84 (d, J = 7.8Hz, 1H), 7.64-7.57 (m, 1H), 5.67 (t, J = 5.7Hz, 1H), 4.64 (d, J = 5.5Hz, 2H).

[0152] Example 2

[0153] Under nitrogen protection, 5 g of substrate 2 (2-bromo-5-chlorophenylacetic acid) was dissolved in 50 mL of tetrahydrofuran to prepare solution A (substrate 2, 20.0 mmol, 1 eq); 100.2 mL of DIBAL-H solution (1 mol / L toluene solution, 5 eq) was prepared as solution B. At 15 °C, DIBAL-H was fed into the coil via pump B at a flow rate of 2 mL / min. When DIBAL-H reached point M1, pump A was turned on to push solution A into the coil at a flow rate of 1 mL / min. After approximately 10 min, the reaction solution flowed out of the coil and was quenched with 1 mol / L NaOH aqueous solution. After complete quenching, the reaction solution was extracted with ethyl acetate (50 mL), and the aqueous phase was washed with ethyl acetate (80 mL * 3). All organic phases were pooled together, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2.45 g of product, with a yield of 82%.

[0154] 1 H NMR (400MHz, DMSO-d6) δ=7.58(d,J=8.5Hz,1H),7.42(d,J=2.5Hz,1H),7.22(dd,J=2.5,8.5Hz,1H),4.77(br t,J=5.0Hz,1H),3.66-3.56(m,2H),2.84(t,J=6.8Hz,2H).

[0155] Example 3

[0156] Under nitrogen protection, dissolve 5 g of substrate 3-(4-bromo-2-methylbenzoic acid) (5 g, 20.0 mmol, 1 eq) in tetrahydrofuran (50 mL) to prepare solution A. Separately prepare DIBAL-H (1 mol / L toluene solution, 5 eq).

[0157] 116 mL of solution B was used. At 15°C, DABAL-H was fed into coil 2 via pump B at a flow rate of 2.3 mL / min. When DABAL-H reached point M1, pump A was turned on to push solution A into coil 2 at a flow rate of 1 mL / min. After approximately 10 minutes, the reaction solution flowed out of coil 2 and was quenched with a 1 mol / L NaOH aqueous solution. After complete quenching, the solution was extracted with ethyl acetate (50 mL), and the aqueous phase was washed with ethyl acetate (80 mL * 3). All organic phases were pooled together, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 4.2 g of product, with a yield of 85%.

[0158] 1H NMR (400MHz, DMSO-d6) δ = 7.38-7.27 (m, 3H), 5.19-5.13 (m, 1H), 4.44 (d, J = 5.4Hz, 2H), 2.22 (s, 3H).

[0159] Example 4

[0160] Under nitrogen protection, 1 g of substrate 4 (2-chloro-6-methylnicotinic acid) was dissolved in 10 mL of tetrahydrofuran to prepare solution A (substrate 4, 5.8 mmol, 1 eq); 20.4 mL of DIBAL-H solution (1 mol / L toluene solution, 3.5 eq) was prepared to prepare solution B. At 15 °C, DIBAL-H was fed into coil 2 through pump B at a flow rate of 0.78 mL / min. When DIBAL-H reached point M1, pump A was turned on to push solution A into the coil at a flow rate of 0.38 mL / min. After about 10 min, the reaction solution flowed out of the coil and was quenched with 1 mol / L NaOH aqueous solution. After the reaction solution was completely quenched, it was extracted with ethyl acetate (50 mL), and the aqueous phase was washed with ethyl acetate (80 mL * 3). All the organic phases were pooled together, and the integrated organic phase was dried with anhydrous sodium sulfate. After filtration and concentration, 0.72 g of product was obtained, with a yield of 73%.

[0161] 1 H NMR (400MHz, DMSO-d6) δ = 7.81 (d, J = 7.6Hz, 1H), 7.28 (d, J = 7.6Hz, 1H), 4.50 (s, 2H), 2.43 (s, 3H).

[0162] Example 5

[0163] Under nitrogen protection, 3 g of substrate 5 (3-furanic acid) was dissolved in 30 mL of tetrahydrofuran to prepare solution A (substrate 5, 26.7 mmol, 1 eq); 107.1 mL of DIBAL-H solution (1 mol / L toluene solution, 4 eq) was prepared as solution B. At 15 °C, DIBAL-H was fed into coil 2 via pump B at a flow rate of 3.57 mL / min. When DIBAL-H reached point M1, pump A was turned on to push solution A into coil 2 at a flow rate of 1 mL / min. After approximately 10 min, the reaction solution flowed out of the coil and was quenched with 1 mol / L NaOH aqueous solution. After complete quenching, the reaction solution was extracted with ethyl acetate (50 mL), and the aqueous phase was washed with ethyl acetate (80 mL * 3). All organic phases were pooled together, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1.5 g of product, with a yield of 57%.

[0164] 1H NMR (400MHz, DMSO-d6) δ = 7.62-7.56 (m, 1H), 7.52 (s, 1H), 6.44 (s, 1H), 4.94 (t, J = 5.3Hz, 1H), 4.34 (d, J = 5.0Hz, 2H).

[0165] Example 6

[0166] Under nitrogen protection, 1 g of substrate 6 (6-trifluoromethylnicotinic acid) was dissolved in 10 mL of tetrahydrofuran to prepare solution A (substrate 6, 5.23 mmol, 1 eq); 15.7 mL of DIBAL-H solution (1 mol / L toluene solution, 3.0 eq) was prepared to prepare solution B. At 15 °C, DIBAL-H was fed into coil 2 through pump B at a flow rate of 0.60 mL / min. When DIBAL-H reached point M1, pump A was turned on to push solution A into the coil at a flow rate of 0.38 mL / min. After about 10 min, the reaction solution flowed out of the coil and was quenched with 1 mol / L NaOH aqueous solution. After the reaction solution was completely quenched, it was extracted with ethyl acetate (50 mL), and the aqueous phase was washed with ethyl acetate (80 mL * 3). All the organic phases were pooled together, and the integrated organic phase was dried with anhydrous sodium sulfate. After filtration and concentration, 0.515 g of product was obtained, with a yield of 56%.

[0167] 1 H NMR (400MHz, DMSO-d6) δ = 8.70 (s, 1H), 8.00 (br d, J = 8.0Hz, 1H), 7.87 (d, J = 8.1Hz, 1H), 5.53 (t, J = 5.6Hz, 1H), 4.65 (d, J = 5.6Hz, 2H).

[0168] The reaction substrates and product yields for Examples 1-6 are shown in Table 1.

[0169] Table 1

[0170]

[0171] This invention utilizes a flow chemistry method for reducing carboxylic acids to alcohols using diisobutylaluminum hydride. By selecting a specific reducing agent and at a certain reaction temperature, carboxylic acids can be gently reduced to alcohols without the risk of material spillage. At the same time, it does not affect other functional groups, exhibits high selectivity, and can obtain the target product with high purity without cumbersome post-processing steps.

[0172] The preferred embodiments of the present invention have been described in detail above. It should be understood that those skilled in the art can make numerous modifications and variations based on the concept of the present invention without creative effort. Therefore, all technical solutions that can be obtained by those skilled in the art based on the concept of the present invention through logical analysis, reasoning, or limited experimentation on the basis of existing technology should be within the scope of protection defined by the claims.

Claims

1. A flow chemistry method for reducing carboxylic acids to alcohols using diisobutylaluminum hydride, characterized in that, Includes the following steps: S1. Dissolve the carboxyl-containing reaction substrate in the first solvent to prepare solution A; S2. Dissolve diisobutylaluminum hydride in the second solvent to prepare solution B; S3. Pump solutions A and B into a three-necked flask. Install a pump body at the rear end of the coil to extract the reaction substrate and diisobutylaluminum hydride from the three-necked flask into the coil to participate in the reaction. The reaction temperature is 15℃ and the reaction time is 10-15 minutes. Extract the gas and reaction liquid generated in the coil together, quench the reaction liquid, and obtain the target product.

2. The flow chemistry method for reducing carboxylic acids to alcohols with diisobutylaluminum hydride as described in claim 1, characterized in that, The first solvent is selected from any one of tetrahydrofuran, dichloromethane, and toluene.

3. The flow chemistry method for reducing carboxylic acids to alcohols with diisobutylaluminum hydride as described in claim 1, characterized in that, The second solvent is selected from toluene or hexane.

4. The flow chemistry method for reducing carboxylic acids to alcohols with diisobutylaluminum hydride as described in claim 1, characterized in that, When the amount of the reaction substrate is 1 molar equivalent, the amount of diisobutylaluminum hydride is 3-5 molar equivalents.

5. The flow chemistry method for reducing carboxylic acids to alcohols with diisobutylaluminum hydride as described in claim 1, characterized in that, The general formula for reaction substrates containing carboxyl groups is as follows: ， R1 is selected from one or more of -H, -Br, -Cl, -F, -NH2, -CF3, -CH3, -I, -OMe, -CH2Br, -NO2, and -OH.

6. The flow chemistry method for reducing carboxylic acids to alcohols with diisobutylaluminum hydride as described in claim 5, characterized in that, The general formula for reaction substrates containing carboxyl groups is as follows: ,in A is selected from any one of -F, -Cl, -Br, -I, -H, -NH2, -CF3, -NO2, -OH, -CH3, -OMe; B is selected from any one of -F, -Cl, -Br, -I, -H, -OMe, -CF3, -CH2Br, -NO2, -OH, -CH3; C is selected from any one of -F, -Cl, -Br, -I, -H, -CF3, -CH3, -CH2Br, -NO2, -OH; E is selected from any one of -F, -Cl, -Br, -I, -H, -CH3, -CF3, -OMe, -NO2, -OH; F is selected from any one of -F, -Cl, -Br, -I, -H, -CH3, -OMe, -NO2, -NH2, -CF3.

7. The flow chemistry method for reducing carboxylic acids to alcohols with diisobutylaluminum hydride as described in claim 6, characterized in that, in A is selected from any one of -F, -Cl, -Br, -I, -H, -CH3, -NH2, -OMe, -NO2; B is selected from any one of -F, -Cl, -Br, -I, -H, -OMe, -CF3, -NO2, -CH3; C is selected from any one of -F, -Br, -H, -CF3, -CH3, -CH2Br, -NO2; E is selected from any one of -I, -H, -CH3, -Br, -OMe, -Cl, -NO2, -OH; F is selected from any one of -F, -Cl, -H, -CH3, -Br, -I, -OMe, -NO2, -NH2.

8. The flow chemistry method for reducing carboxylic acids to alcohols with diisobutylaluminum hydride as described in claim 1, characterized in that, Carboxyl-containing reaction substrates are: 。 9. The flow chemistry method for reducing carboxylic acids to alcohols with diisobutylaluminum hydride as described in claim 1, characterized in that, The general formula for reaction substrates containing carboxyl groups is as follows: ， R2 is selected from one or more of -H, -Br, -Cl, -F, -NH2, -CF3, -CH3, -I, -OMe, -CH2Br, -NO2, and -OH.

10. The flow chemistry method for reducing carboxylic acids to alcohols with diisobutylaluminum hydride as described in claim 9, characterized in that, The general formula for reaction substrates containing carboxyl groups is as follows: ， Wherein G is selected from any one of -F, -Cl, -Br, -I, -H, -NH2, -CF3, -NO2, -OH, -CH3, -OMe; H is selected from any one of -F, -Cl, -Br, -I, -H, -OMe, -CF3, -CH2Br, -NO2, -OH, -CH3; I is selected from any one of -F, -Cl, -Br, -I, -H, -CF3, -CH3, -CH2Br, -NO2, -OH; J is selected from any one of -F, -Cl, -Br, -I, -H, -CH3, -OMe, -NO2, -NH2, -CF3.

11. The flow chemistry method for reducing carboxylic acids to alcohols with diisobutylaluminum hydride as described in claim 1, characterized in that, Carboxyl-containing reaction substrates are: 。 12. The flow chemistry method for reducing carboxylic acids to alcohols with diisobutylaluminum hydride as described in claim 1, characterized in that, Carboxyl-containing reaction substrates are: 。

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