Method for preparing β-hydroxy acid or its derivative by electrocarboxylation reaction of epoxide and carbon dioxide, compound prepared thereby, and application thereof

Abstract

The present invention discloses a method for preparing β-hydroxy acids and / or β-hydroxy acid derivatives by electrocarboxylation of epoxides with carbon dioxide, as well as the compounds prepared thereby and their applications. The method of the present invention comprises the following steps: in a CO2 atmosphere, after dissolving an epoxide and a supporting electrolyte in a solvent, an electrocarboxylation reaction occurs under the condition of energization, followed by acidification and optionally post-treatment to obtain the β-hydroxy acids and / or β-hydroxy acid derivatives. The present invention adopts an electrocatalytic method to carry out ring-opening carboxylation of reaction substrates by regulating the magnitude of the electrolysis current and the electrode material. This electrochemical synthesis method features mild reaction conditions, being clean and green, and having simple reaction operations.

Description

Technical Field

[0001] The present invention relates to the technical field of organic chemistry. Further, it relates to a method for preparing β-hydroxy acids and / or β-hydroxy acid derivatives by electrocarboxylation of epoxides with carbon dioxide, as well as the compounds prepared thereby and their applications. Background Art

[0002] β-Hydroxy acids are essential structures in many bioactive compounds, small molecule drugs, and natural products. Therefore, developing innovative and efficient methods for synthesizing β-hydroxy acids will have great scientific and practical value. Some existing strategies for constructing β-hydroxy acid derivatives, such as decarboxylative Aldol reactions, catalytic hydrogenation, Reformatsky reactions, etc., usually require multiple steps of synthesis and transformation, and have limited functional group tolerance. Therefore, developing direct and efficient methods for constructing β-hydroxy acids remains highly desirable and challenging. At the same time, epoxides are electrophilic molecules that are easily obtained in organic synthesis and have a high tendency to undergo ring-opening reactions; CO2 is abundant in reserves, inexpensive and readily available, and is a green C1 synthon. Conceptually, the direct carboxylation reaction of epoxide ring-opening with CO2 can efficiently, greenly, and atom-economically achieve the synthesis of β-hydroxy acids. However, this reaction poses great challenges: 1) Epoxides are electrophilic reagents, and the reaction with CO2 requires a polarity inversion to nucleophilically attack CO2 for carboxylation; 2) The site selectivity of epoxy ring-opening; 3) CO2 molecules have good thermodynamic stability and are difficult to activate. These factors limit its application in the field of synthetic chemistry. Summary of the Invention

[0003] To solve the problems in the prior art, the present invention provides a method for preparing β-hydroxy acids and / or β-hydroxy acid derivatives by electrocarboxylation of epoxides with carbon dioxide, as well as the compounds prepared thereby and their applications. The present invention adopts an electrochemical catalysis method to carry out ring-opening carboxylation of the reaction substrates by regulating the magnitude of the electrolysis current and the electrode material. This electrochemical synthesis method has the characteristics of mild reaction conditions, clean and green, and simple reaction operation.

[0004] One object of the present invention is to provide a method for preparing β-hydroxy acids and / or β-hydroxy acid derivatives by electrocarboxylation of epoxides with carbon dioxide, comprising the following steps:

[0005] In a CO2 atmosphere, after dissolving the epoxide and the supporting electrolyte in a solvent, an electrocarboxylation reaction occurs under the condition of energization, followed by acidification and optionally post-treatment to obtain the β-hydroxy acids and / or β-hydroxy acid derivatives.

[0006] In the method of the present invention, preferably:

[0007] The epoxide has the following general structural formula:

[0008]

[0009] Ar is selected from a substituted or unsubstituted aryl group; R 1 , R 2 , R 3 are each independently selected from hydrogen, an alkyl group, and an aryl group;

[0010] R 4 is selected from hydrogen, an alkyl group, a fatty group, a halogen atom, a nitro group, a cyano group, an aryl group, and an amide group;

[0011] n is selected from any integer from 1 to 4, that is, the number of carbon atoms forming the ring on the oxygen-containing ring in the epoxide is 2 to 5;

[0012] Preferably, the carbon atoms forming the ring on the oxygen-containing ring in the epoxide are single carbon-carbon bonds.

[0013] In the method of the present invention, preferably:

[0014] n is 1;

[0015] Preferably, the epoxide has the following general structural formula:

[0016]

[0017] R 1 , R 2 , R 3 are each independently selected from hydrogen, an alkyl group having 1 to 5 carbon atoms, and a phenyl group; and at least one of R2 and R3 is selected from hydrogen;

[0018] R 4 is selected from hydrogen, an alkyl group, a fatty group, a halogen atom, a nitro group, a cyano group, an aryl group, and an amide group;

[0019] Preferably, the carbon atoms forming the ring on the oxygen-containing ring in the epoxide are single carbon-carbon bonds.

[0020] In the method of the present invention, preferably:

[0021] The epoxide of the general structural formula 2 includes the following compounds:

[0022]

[0023] In the method of the present invention, preferably:

[0024] n is 2 to 4;

[0025] Preferably, the epoxide has the following general structural formula:

[0026]

[0027] The said R 1 is selected from hydrogen and unsubstituted phenyl;

[0028] The epoxides of the said general structural formula 2 include the following compounds:

[0029]

[0030] In the method of the present invention, preferably:

[0031] The said supporting electrolyte is selected from at least one of halogen salts; and / or,

[0032] The said supporting electrolyte is 50%-100% molar equivalent of the epoxide;

[0033] Preferably, the said halogen salt is selected from at least one of tetraalkylhalogen salts or inorganic halogen salts;

[0034] More preferably, the said tetraalkylhalogen salt is selected from at least one of tetraethylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium tetrafluoroborate; and / or,

[0035] The said inorganic halogen salt is selected from at least one of sodium iodide, potassium iodide, ammonium iodide.

[0036] In the method of the present invention, preferably:

[0037] The said solvent is selected from at least one of amide solvents, nitrile solvents, pyrrolidone solvents; and / or,

[0038] The said solvent is selected from at least one of amide solvents, nitrile solvents, pyrrolidone solvents; and / or, the concentration of the epoxide in the solvent is 0.05-0.4 mol / L;

[0039] Preferably, the concentration of the epoxide in the solvent is 0.1-0.2 mol / L; and / or,

[0040] The said solvent is selected from at least one of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, N-methylpyrrolidone.

[0041] Preferably, the said solvent is selected from at least one of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, N-methylpyrrolidone.

[0042] In the method of the present invention, preferably:

[0043] When carrying out the electrified reaction, a constant current is passed in.

[0044] Preferably,

[0045] The constant current is 1 - 30 mA; and / or,

[0046] The energized reaction time is 0.5 - 20 h; and / or,

[0047] The energized reaction temperature is -20 - 50 °C; and / or,

[0048] More preferably,

[0049] The constant current is 5 - 15 mA; and / or,

[0050] The energized reaction time is 3.5 - 14 h; and / or,

[0051] The energized reaction temperature is -10 - 30 °C; and / or,

[0052] During the energized reaction, among the electrodes used, the cathode material is selected from graphite felt and platinum sheet; the anode material is selected from magnesium sheet, zinc sheet, aluminum sheet, and carbon felt; and / or,

[0053] During the acidification, the concentration of the acid used is 1 - 2 mol / L. Preferably, the acid used is hydrochloric acid; and / or,

[0054] The post-treatment includes directly extracting and concentrating to obtain a crude product; and a step of purifying the obtained crude product; or the post-treatment includes directly extracting and concentrating to obtain a crude product; performing an esterification reaction on the obtained crude product, preparing it into a methyl carboxylate, and then performing a purification step.

[0055] Preferably, the purification method is column chromatography.

[0056] The second object of the present invention is to provide a β-hydroxy acid compound and / or a β-hydroxy acid derivative prepared by the method described in the first object of the present invention; the β-hydroxy acid compound is a compound formed after ring-opening carboxylation of the epoxide; the β-hydroxy acid derivative is a compound formed by further esterification of the β-hydroxy acid compound, preferably a methyl β-hydroxy acid compound;

[0057] Preferably, the β-hydroxy acid compound and / or β-hydroxy acid derivative of the present invention are as follows:

[0058]

[0059] The third object of the present invention is to provide the application of the method described in the first object of the present invention in constructing a drug molecule containing a β-hydroxy acid and / or a β-hydroxy acid derivative, or the application of the β-hydroxy acid compound and / or β-hydroxy acid derivative described in the second object of the present invention as a substrate in synthesizing a drug molecule containing a β-hydroxy acid and / or a β-hydroxy acid derivative.

[0060] The reaction mechanism of the present invention is as follows:

[0061]

[0062] Magnesium ions are continuously generated on the anode and combine with the epoxide to form intermediate I. Two possible pathways are proposed in the initial step. When the substrate is more positive than the reduction potential of CO2, the substrate is preferentially reduced at the cathode to form intermediate II (path A). When the substrate is more negative than the reduction potential of CO2, CO2 generates a CO2 radical anion through a single-electron reduction process at the cathode; the generated CO2 radical anion has strong reducibility, and the substrate is reduced by the CO2 radical anion through single-electron transfer to form intermediate II (path B). Intermediate II undergoes C-O bond cleavage to obtain radical intermediate III. Subsequently, intermediate III is further reduced by a single electron and nucleophilically attacks CO2 to form intermediate IV. Finally, hydrochloric acid aqueous solution is added to the system for acidification to ultimately generate β-hydroxy acid;

[0063] In the present invention, some carboxylic acids are not easily separated and purified, and the generated carboxylic acids are further converted into esters for purification.

[0064] In the present invention, the endpoints and any values within the disclosed ranges are not limited to the exact ranges or values. These ranges or values should be understood to include values close to these ranges or values. For numerical ranges, the endpoint values of each range, between the endpoint values of each range and individual point values, and between individual point values can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be regarded as specifically disclosed herein. In the following text, in principle, various technical solutions can be combined with each other to obtain new technical solutions, which should also be regarded as specifically disclosed herein.

[0065] Compared with the prior art, the present invention has at least the following advantages:

[0066] 1. In the present invention, an epoxide, an electrolyte, and a supporting electrode are added to a container, and the supporting electrolyte enhances the conductivity of the solvent. A constant current is passed through the two electrodes at room temperature. The ring-opening carboxylation of the epoxide is efficiently achieved, and this method has mild reaction conditions, wide substrate adaptability, can be applied to a wide range of drug molecular structures, and has good industrial application prospects.

[0067] 2. In the present invention, by adjusting the magnitude of the current and the electrode material of the anode, the reaction substrate can be selectively electrolyzed. It can be simultaneously applied to aryl-substituted epoxides and aryl-substituted cyclic ethers, and is compatible with ester groups, nitro groups, and amides to obtain β-hydroxy acids in relatively high yields.

[0068] 3. The electrochemical synthesis method of the present invention can be applied to high-current conditions. At a constant current of 50 mA, it can still provide good yields and selectivities, and the reaction can be completely converted within 14 h.

[0069] 4. The method of the present invention has a high tolerance to substrate functional groups. For different substituents, whether electron-withdrawing groups or electron-donating groups, it shows good reactivity, and the target products have high yields and selectivities. Moreover, it also shows good compatibility with complex late-modified drug molecules and natural products.

[0070] In summary, the present invention: a) converts CO2 into high-value-added organic small molecules through epoxy ring-opening carboxylation; b) has high chemoselectivity and exclusive regioselectivity; c) uses electrochemistry as an efficient and scalable preparation technology, with prospects for industrial application; (d) the preparation method of the present invention is applied to the post-modification carboxylation of natural products and drug derivatives. It is worth noting that this simple and selective electroreductive carboxylation strategy is also applicable to the synthesis of γ-hydroxy acid, σ-hydroxy acid, and ε-hydroxy acid derivatives. The electrochemical synthesis method of the present invention for electrolytic ring-opening carboxylation of reaction substrates has the characteristics of mild reaction conditions, clean and green, and simple reaction operation. Detailed implementation manners

[0071] The present invention will be specifically described below in conjunction with specific embodiments. It is necessary to point out here that the following embodiments are only for further illustration of the present invention and cannot be construed as limiting the protection scope of the present invention. Some non-essential improvements and adjustments made by those skilled in the art according to the content of the present invention still fall within the protection scope of the present invention.

[0072] In addition, it should be noted that the various specific technical features described in the following detailed implementation manners can be combined in any suitable manner without contradiction. To avoid unnecessary repetition, the present invention will not separately describe various possible combination methods. In addition, any combination can be made between various different embodiments of the present invention as long as it does not violate the idea of the present invention. The technical solutions formed thereby belong to a part of the original public content of this specification and also fall within the protection scope of the present invention.

[0073] If there is no special limitation on the raw materials used in the embodiments, then they are all disclosed in the prior art, for example, they can be directly purchased or prepared according to the preparation methods disclosed in the prior art.

[0074] Example 1

[0075] An electrochemical synthesis method for preparing β-hydroxy acid or its derivative by electrocarboxylation reaction of an epoxide with carbon dioxide provided by a preferred embodiment of the present invention is as follows:

[0076] In a 15 mL reaction tube, fix the electrodes: magnesium sheet anode (10 mm wide, 20 mm long, 0.8 mm thick), platinum sheet cathode (10 mm wide, 15 mm long, 0.1 mm thick) (the electrodes are fixed on both sides of the tube with rubber stoppers). Add a magnetic stir bar, epoxide (0.3 mmol, 1.0 equiv), n Bu4NI (110.8 mg, 0.3 mmol, 1.0 equiv) to the reaction tube in sequence. Replace the air in the reaction tube with CO2 through a double-tube gas guiding system (repeated three times, 3 minutes each time), and then add anhydrous DMF (3.0 mL) through a syringe under a CO2 atmosphere. Connect a CO2 balloon, start the stirrer, and after all the solids are completely dissolved, immerse the electrodes into the solution. Electrolyze at a constant current of 10.0 mA for 3.5 h. Then, acidify the reaction mixture with an aqueous HCl solution (2.0 mol / L), extract the aqueous phase with ethyl acetate (5×10 mL), combine the organic phases, wash with saturated brine, dry over anhydrous MgSO4, filter, and concentrate under vacuum. The crude product is purified by column chromatography to obtain the desired β-hydroxy acid product.

[0077] In Example 1, some of the β-hydroxy acid products have relatively large polarity, and there is a large loss during direct column chromatography separation. The inventor converts the crude product into the corresponding methyl carboxylate, that is, generates the corresponding carboxylic acid derivative and then purifies it. The steps are as follows: Dissolve the crude product in a mixed solvent (ether: methanol = 3 mL: 1 mL), and under an ice bath, dropwise add a TMSCH2N2 solution and stir for 2 h under an ice bath. Then, remove the solvent and purify by column chromatography to obtain the desired carboxylic acid derivative product, such as the 2d, 3a - 3c compounds described below.

[0078] The results of the β-hydroxy acids or their derivatives in Example 1 are as follows:

[0079]

[0080] As can be seen from the above, aryl epoxides containing para (1a - e) or meta (1g - h)) substituents and simple styrene oxide (1f) can all smoothly generate the desired products. It is worth noting that functional groups sensitive to electroreduction conditions, including ester groups (2a, 2g), nitro groups (2e), cyano groups (2h), and amide groups (2d), are all compatible under standard conditions, indicating that this electroreduction process has good functional group compatibility. Naphthalene ring-substituted epoxides can also smoothly undergo reactions, such as 2i and 2j (81%, 76%).

[0081] In addition, at lower temperatures, sterically hindered 1,1-disubstituted aryl epoxides (1k, 1q) can smoothly undergo electrocarboxylation reactions under standard conditions to form β-hydroxy acids containing quaternary carbon centers, with high chemoselectivity and good yields (2k, 2q; 76%, 85%). In addition, we are pleased to observe that 1,2-disubstituted and 1,2-trisubstituted aryl epoxides effectively undergo this transformation, allowing the formation of polysubstituted β-hydroxy acids 2r, as a single diastereomer 2s in 87% yield; as a 5:1 mixture of two diastereomers in 78% yield.

[0082] Notably, this simple and selective electroreductive carboxylation strategy is also applicable to the synthesis of γ-hydroxy acids, σ-hydroxy acids, and ε-hydroxy acid derivatives (corresponding compounds 3a - 3c).

[0083] Example 2

[0084] An electrochemical synthesis method for preparing β-hydroxy acids by electrocarboxylation reaction of epoxides with carbon dioxide provided by a preferred embodiment of the present invention comprises the following specific steps:

[0085] In a 15 mL reaction tube, fix the electrodes: magnesium sheet anode (10 mm wide, 20 mm long, 0.8 mm thick), platinum sheet cathode (10 mm wide, 15 mm long, 0.1 mm thick) (the electrodes are fixed on both sides of the tube with rubber stoppers). Sequentially add a magnetic stir bar, epoxide (0.3 mmol, 1.0 equiv), n Bu4NI (110.8 mg, 0.3 mmol, 1.0 equiv) into the reaction tube. Replace the air in the reaction tube with CO2 through a double-tube gas guiding system (repeated three times, 3 minutes each time), and then add anhydrous DMF (3.0 mL) through a syringe under a CO2 atmosphere. Connect a CO2 balloon, start the stirrer, and after all solids are completely dissolved, immerse the electrodes into the solution. Electrolyze at a constant current of 10.0 mA for 3.5 h. Then, acidify the reaction mixture with an HCl aqueous solution (2.0 N), extract the aqueous phase with ethyl acetate (5 × 10 mL), combine the organic phases, wash with saturated brine, dry with anhydrous MgSO4, filter, and concentrate under vacuum. The crude product is purified by column chromatography to obtain the desired β-hydroxy acid product.

[0086] Some of the β-hydroxy acid products in Example 1 have relatively high polarity, and there is a large loss during direct column chromatography separation. The inventor converts the crude product into the corresponding methyl carboxylate, that is, generates the corresponding carboxylic acid derivative and then purifies it. The steps are as follows: Dissolve the crude product in a mixed solvent (ether: methanol: 3 mL: 1 mL), and under an ice bath, dropwise add a TMSCH2N2 solution and stir for 2 h under the ice bath. Then, remove the solvent and purify by column chromatography to obtain the desired carboxylic acid derivative product, such as compound 2t described below.

[0087] The results of the β-hydroxy acid or its derivative in Example 2 are as follows:

[0088]

[0089] As can be seen from the above, this reaction can be applicable to the post-modification of complex drugs, such as the reductive carboxylation of ketoprofen, fenbufen, and derivatives of menthol (2t, 2u, 2v); and the derivative carboxylation reaction of complex natural products (2w, 2x, 2y, 2z).

[0090] Examples 3 - 15

[0091] Gram-scale experiment:

[0092]

[0093] The reaction conditions were changed and the yields were compared.

[0094] Reaction conditions: Reaction substrate 1 (0.3 mmol), tetrabutylammonium iodide (0.3 mmol), N,N-dimethylformamide (3 mL), platinum sheet as the cathode, magnesium sheet as the anode, constant current electrolysis at room temperature (I = 10 mA).

[0095]

[0096] The changes in reaction conditions and their yields are shown in the following table:

[0097] Table 1

[0098]

[0099]

[0100] The yields in Table 1 above are NMR yields, and the isolated yields are in parentheses.

[0101] As can be seen from Table 1 above, under the reaction conditions of the present invention, the difference rate corresponding to epoxy ring-opening carboxylation is as high as 94% (the isolated yield is in parentheses). A series of control experiments show that changing the electrode material will reduce the yield, and no target carboxylation product is formed when using a non-sacrificial anode material. When using other supporting electrolytes or solvents, the yield decreases significantly. Decreasing the current results in a slight decrease in the yield, and increasing the current significantly reduces the yield. The investigation of the current shows that 10 mA is the optimal current value.

[0102] The parameters of some alkyl deuterated products synthesized in the present invention are as follows:

[0103]

[0104] Product 2a, property: white solid;

[0105] 1 1H NMR (CDCl3, 400 MHz) δ = 8.02 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 4.16 (dd, J = 10.7, 8.2 Hz, 1H), 3.99–3.89 (m, 5H). 13 13C NMR (CDCl3, 100 MHz) δ = 176.8, 166.7, 140.0, 130.2, 129.9, 128.4, 64.0, 53.6, 52.3. HRMS (ESI): Calcd for C 11 H 11 O5 - [M−H] - 223.0612, found 223.0611.

[0106]

[0107] Product 2b, property: white solid;

[0108] 1 1H NMR (DMSO-d6, 400 MHz) δ = 12.49 (s, 1H), 7.66–7.62 (m, 4H), 7.48–7.45 (m, 2H), 7.43–7.33 (m, 3H), 5.02 (s, 1H), 3.97 (t, J = 8.4 Hz, 1H), 3.72–3.70 (m, 1H), 3.65–3.62 (m, 1H). 13 13C NMR (DMSO-d6, 100 MHz) δ = 174.2, 140.3, 139.5, 136.8, 129.4, 129.2, 127.9, 127.2, 127.1, 63.8, 54.4. HRMS (ESI): Calcd for C 15 H 13 O3 - [M−H] - 241.0870, found 241.0875.

[0109]

[0110] Product 2c, property: colorless liquid;

[0111] 11H NMR (CDCl3, 400 MHz) δ = 7.25–7.23 (m, 2H), 7.03 (t, J = 8.6 Hz, 2H), 4.14–4.08 (m, 1H), 3.85–3.79 (m, 2H), 3.72 (s, 3H), 2.35 (s, 1H). 13 13C NMR (CDCl3, 100 MHz) δ = 173.5, 162.3 (d, J = 246.6 Hz), 131.4 (d, J = 3.4 Hz), 129.8 (d, J = 8.5 Hz), 115.8 (d, J = 22.0 Hz), 64.6, 53.1, 52.3. 19 19F NMR (CDCl3, 375 MHz) δ = -115.3. HRMS (ESI): Calcd for C 10 H 11 FNaO3 + [M+Na] + 221.0584, found 221.0584.

[0112]

[0113] Product 2d, property: white solid;

[0114] 1 1H NMR (CDCl3, 400 MHz) δ = 7.41 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 4.13 (t, J = 10.6 Hz, 1H), 3.92–3.87 (m, 1H), 3.86–3.81 (m, 1H), 3.73 (s, 3H), 3.12 (s, 3H), 3.00 (s, 3H), 2.42 (s, 1H). 13 13C NMR (CDCl3, 100 MHz) δ = 173.2, 171.1, 137.1, 135.8, 128.3, 127.6, 64.4, 53.7, 52.3. HRMS (ESI): Calcd for C 13 H 17 NNaO4 + [M+Na] + 274.1050, found 274.1053.

[0115]

[0116] Product 2e, property: white solid;

[0117] 11H NMR (CDCl3, 400 MHz) δ = 8.22 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 4.16 (dd, J = 10.6, 7.4 Hz, 1H), 4.00–3.91 (m, 2H), 3.76 (s, 3H), 2.34 (s, 1H). 13 13C NMR (CDCl3, 100 MHz) δ = 172.4, 143.0, 129.3, 127.3, 124.0, 64.1, 53.5, 52.6. HRMS (ESI): Calcd for C 10 H 11 NNaO5 + [M+Na] + 248.0529, found 248.0524.

[0118]

[0119] Product 2f, property: colorless liquid;

[0120] 1 1H NMR (CDCl3, 400 MHz) δ = 7.39–7.29 (m, 5H), 4.16 (t, J = 9.2 Hz, 1H), 3.90–3.82 (m, 2H), 3.72 (s, 3H), 2.84 (s, 1H). 13 13C NMR (CDCl3, 100 MHz) δ = 173.7, 135.6, 128.9, 128.2, 127.8, 64.5, 54.0, 52.2. HRMS (ESI): Calcd for C 10 H 12 NaO3 + [M+Na] + 203.0679, found 203.0680.

[0121]

[0122] Product 2g, property: white solid;

[0123] 1 1H NMR (DMSO-d6, 400 MHz) δ = 7.92 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 6.5 Hz, 1H), 7.51–7.47 (m, 1H), 3.96–3.91 (m, 1H), 3.86 (s, 3H), 3.79–3.76 (m, 1H), 3.68–3.64 (m, 1H). 1313C NMR (DMSO-d6, 100 MHz) δ = 173.8, 166.6, 138.4, 133.8, 130.2, 129.3, 129.2, 128.4, 63.6, 54.3, 52.6. HRMS (ESI): Calcd for C 11 H 11 O5 - [M-H] - 223.0612, found 223.0615.

[0124]

[0125] Product 2h, property: brown solid;

[0126] 1 1H NMR (CDCl3, 400 MHz) δ = 7.62–7.55 (m, 3H), 7.47 (t, J = 7.7 Hz, 1H), 4.14–4.08 (m, 1H), 3.91–3.87 (m, 2H), 3.74 (s, 3H), 2.62 (s, 1H). 13 13C NMR (CDCl3, 100 MHz) δ = 172.5, 137.3, 132.9, 131.9, 131.4, 129.6, 118.4, 112.9, 64.1, 53.3, 52.5. HRMS (ESI): Calcd for C 11 H 12 NO3 + [M+H] + 206.0812, found 206.0814.

[0127]

[0128] Product 2i, property: white solid;

[0129] 1 1H NMR (DMSO-d6, 400 MHz) δ = 12.46 (s, 1H), 7.93–7.87 (m, 3H), 7.83 (s, 1H), 7.54–7.48 (m, 3H), 5.01 (s, 1H), 4.05 (t, J = 9.4 Hz, 1H), 3.85 (t, J = 6.9 Hz, 1H), 3.73–3.69 (m, 1H). 1313C NMR (DMSO-d6, 100 MHz) δ = 173.7, 134.7, 132.9, 132.1, 127.8, 127.5, 127.4, 126.7, 126.4, 126.1, 125.8, 63.3, 54.4. HRMS (ESI): Calcd for C 13 H 11 O3 - [M-H] - 215.0714, found 215.0712.

[0130]

[0131] Product 2j, property: white solid;

[0132] 1 1H NMR (CDCl3, 400 MHz) δ = 8.14 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.62–7.52 (m, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.41 (d, J = 6.3 Hz, 1H), 4.71 (dd, J = 9.2, 4.6 Hz, 1H), 4.34 (dd, J = 11.3, 9.2 Hz, 1H), 3.93 (dd, J = 11.3, 4.6 Hz, 1H), 3.74 (s, 3H), 2.54 (s, 1H). 13 13C NMR (CDCl3, 100 MHz) δ = 174.4, 134.1, 131.8, 131.4, 129.1, 128.4, 126.7, 125.9, 125.5, 125.4, 122.9, 64.2, 52.3, 49.7. HRMS (ESI): Calcd for C 14 H 14 NaO3 + [M+Na] + 253.0835, found 253.0825.

[0133]

[0134] Product 2k, property: white solid;

[0135] 11H NMR (DMSO-d6, 400 MHz) δ = 12.42 (s, 1H), 7.66–7.62 (m, 4H), 7.48–7.42 (m, 4H), 7.38–7.34 (m, 1H), 5.01 (s, 1H), 4.01 (d, J = 10.2 Hz, 1H), 3.71 (d, J = 10.2 Hz, 1H), 1.54 (s, 3H). 13 13C NMR (DMSO-d6, 100 MHz) δ = 176.0, 141.4, 139.8, 138.4, 128.9, 127.3, 126.8, 126.6, 126.5, 67.2, 51.7, 20.8. HRMS (ESI): Calcd for C 16 H 15 O3 - [M-H] - 255.1027, found 255.1025.

[0136]

[0137] Product 2l, property: white solid;

[0138] 1 1H NMR (CDCl3, 400 MHz) δ = 7.81 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.3 Hz, 2H), 6.37 (s, 1H), 3.90 (d, J = 11.4 Hz, 1H), 3.73 (s, 3H), 3.53 (d, J = 11.3 Hz, 1H), 1.47 (s, 3H). 13 13C NMR (CDCl3, 100 MHz) δ = 179.2, 167.0, 145.2, 129.9, 129.1, 126.5, 68.6, 52.6, 52.3, 20.2. HRMS (ESI): Calcd for C 12 H 13 O5 - [M-H] - 237.0768, found 237.0765.

[0139]

[0140] Product 2m, property: white solid;

[0141] 11H NMR (CDCl3, 400 MHz) δ = 7.65 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 3.99 (d, J = 11.4 Hz, 1H), 3.75–3.72 (m, 4H), 2.66 (s, 1H), 1.65 (s, 3H). 13 13C NMR (CDCl3, 100 MHz) δ = 175.5, 145.9, 132.3, 127.3, 118.5, 111.3, 69.0, 52.9, 52.6, 20.1. HRMS (ESI): Calcd for C 12 H 14 NO3 + [M + H] + 220.0968, found 220.0965.

[0142]

[0143] Product 2n, property: white solid;

[0144] 1 1H NMR (CDCl3, 400 MHz) δ = 7.92 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.54–7.51 (m, 1H), 7.46–7.39 (m, 3H), 4.43 (d, J = 11.5 Hz, 1H), 3.75 (d, J = 11.5 Hz, 1H), 1.86 (s, 3H). 13 13C NMR (CDCl3, 100 MHz) δ = 182.7, 135.6, 134.4, 131.3, 129.6, 129.0, 126.3, 125.5, 125.3, 124.7, 123.6, 68.1, 51.5, 22.5. HRMS (ESI): Calcd for C 14 H 13 O3 - [M - H] - 229.0870, found 229.0867.

[0145]

[0146] Product 2o, property: white solid;

[0147] 11H NMR (CDCl3, 400 MHz) δ = 7.89–7.85 (m, 4H), 7.53–7.49 (m, 3H), 4.25 (d, J = 11.5 Hz, 1H), 3.82 (d, J = 11.5 Hz, 1H), 1.83 (s, 3H). 13 13C NMR (CDCl3, 100 MHz) δ = 176.5, 140.3, 133.3, 132.2, 128.4, 128.0, 127.7, 126.5, 126.3, 125.5, 125.1, 67.6, 52.5, 21.4. HRMS (ESI): Calcd for C 14 H 13 O3 - [M - H] - 229.0870, found 229.0871.

[0148]

[0149] Product 2p, property: white solid;

[0150] 1 1H NMR (CDCl3, 400 MHz) δ = 7.42 (d, J = 7.8 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 3.83 (d, J = 11.4 Hz, 1H), 3.55–3.50 (m, 4H), 2.44 (s, 1H), 1.48 (s, 3H). 13 13C NMR (CDCl3, 100 MHz) δ = 175.9, 144.5, 129.6 (q, J = 32.5 Hz), 125.5 (q, J = 3.6 Hz), 124.0 (q, J = 272.2 Hz), 69.3, 52.7, 52.5, 20.1. 19 19F NMR (CDCl3, 375 MHz) δ = -63.5. HRMS (ESI): Calcd for C 12 H 14 FO3 + [M + H] + 263.0890, found 263.0891.

[0151]

[0152] Product 2q, property: white solid;

[0153] 11H NMR (CDCl3, 400 MHz) δ = 7.27–7.17 (m, 10H), 4.25 (s, 2H), 3.71 (s, 3H), 2.65 (s, 1H). 13 13C NMR (CDCl3, 100 MHz) δ = 175.1, 140.5, 128.8, 128.3, 127.4, 68.3, 62.2, 52.7. HRMS (ESI): Calcd for C 16 H 16 NaO3 + [M+Na] + 279.0992, found 279.0996.

[0154]

[0155] Product 2r, property: white solid;

[0156] 1 1H NMR (CDCl3, 400 MHz) δ = 7.95 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 4.4 (d, J = 6.2 Hz, 1H), 3.88 (s, 3H), 3.60 (d, J = 6.2 Hz, 1H), 1.16 (d, J = 6.2 Hz, 3H). 13 13C NMR (CDCl3, 100 MHz) δ = 176.5, 167.0, 140.0, 129.8, 129.5, 129.5, 68.4, 58.3, 52.3, 20.5. HRMS (ESI): Calcd for C 12 H 13 O5 - [M-H] - 237.0768, found 237.0766.

[0157]

[0158] Product 2s, property: white solid;

[0159] 1 1H NMR (CDCl3, 400 MHz) δ = 8.02 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 4.38 (q, J = 6.3 Hz, 1H), 3.92 (s, 3H), 1.66 (s, 3H), 1.05 (d, J = 6.4 Hz, 3H). 1313C NMR(CDCl3, 100 MHz) δ = 180.5, 166.9, 143.9, 129.5, 129.3, 127.6, 72.0, 55.5, 52.2, 18.6, 17.7. HRMS(ESI): Calcd for C 13 H 15 O5 - [M - H] - 251.0925, found 251.0921.

[0160]

[0161] Product 2t, property: white solid;

[0162] 1 1H NMR(CDCl3, 400 MHz) δ = 7.33–7.13(m, 10H), 4.31(s, 2H), 3.77(s, 3H), 3.69–3.62(m, 4H), 2.89(s, 1H), 1.45(d, J = 7.2 Hz, 3H). 13 13C NMR(CDCl3, 100 MHz) δ = 174.9, 174.8, 140.9, 140.5, 128.8, 128.7, 128.5, 128.4, 128.3, 128.2, 127.7, 127.4, 126.4, 126.3, 68.2, 62.2, 52.7, 52.0, 45.4, 18.7. HRMS(ESI): Calcd for C 20 H 22 NaO5 + [M + Na] + 365.1359, found 365.1357.

[0163]

[0164] Product 2u, property: white solid;

[0165] 1 1H NMR(CDCl3, 400 MHz) δ = 7.62(d, J = 8.3 Hz, 2H), 7.56(d, J = 7.4 Hz, 2H), 7.48–7.42(m, 4H), 7.37(t, J = 8.0 Hz, 1H), 5.00(d, J = 11.3 Hz, 1H), 4.64(d, J = 11.6 Hz, 1H), 2.82–2.72(m, 2H), 2.69–2.60(m, 1H), 2.49–2.41(m, 1H). 1313C NMR(CDCl3, 100 MHz) δ = 176.9, 169.6, 141.6, 139.9, 135.2, 128.9, 128.0, 127.8, 127.1, 126.5, 72.6, 48.2, 28.1, 27.3. HRMS(ESI): Calcd for C 18 H 17 O4 + [M + H] + 297.1121, found 297.1119.

[0166]

[0167] Product 2v, property: white solid;

[0168] 1 1H NMR(DMSO-d6, 400 MHz) δ = 12.52(s, 1H), 7.92(d, J = 8.1 Hz, 2H), 7.47(d, J = 8.1 Hz, 2H), 4.87–4.82(m, 1H), 4.04–3.93(m, 1H), 3.77(t, J = 6.0 Hz, 1H), 3.66–3.61(m, 1H), 2.07–1.93(m, 1H), 1.88–1.85(m, 1H), 1.67(d, J = 11.2 Hz, 2H), 1.55–1.50(m, 2H), 1.13–1.04(m, 2H), 0.94–0.86(m, 7H), 0.74(d, J = 6.8 Hz, 3H). 13 13C NMR(CDCl3, 100 MHz) δ = 177.4, 165.7, 139.8, 130.6, 130.2, 128.4, 75.1, 64.0, 53.7, 47.3, 40.9, 34.3, 31.4, 26.5, 23.6, 22.0, 20.8, 16.5. HRMS(ESI): Calcd for C 20 H 27 O5 - [M - H] - 347.1864, found 347.1860.

[0169]

[0170] Product 2w, property: white solid;

[0171] 11H NMR (DMSO-d6, 400 MHz) δ = 8.76 (d, J = 6.0 Hz, 1H), 7.84 (d, J = 7.2 Hz, 2H), 7.41 (d, J = 7.3 Hz, 2H), 4.52–4.47 (m, 1H), 3.95 (t, J = 8.6 Hz, 1H), 3.76–3.72 (m, 1H), 3.65–3.60 (m, 4H), 1.41 (d, J = 6.7 Hz, 3H). 13 13C NMR (DMSO-d6, 100 MHz) δ = 173.8, 173.6, 166.5, 141.2, 133.0, 128.5, 128.0, 63.7, 54.6, 52.3, 48.7, 17.2. HRMS (ESI): Calcd for C 14 H 16 NO3 - [M-H] - 294.0983, found 294.0983

[0172]

[0173] Product 2x, property: white solid;

[0174] 1 1H NMR (DMSO-d6, 400 MHz) δ = 8.57 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 7.4 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H), 4.31 (t, J = 7.6 Hz, 1H), 3.96 (t, J = 8.4 Hz, 1H), 3.77–3.73 (m, 1H), 3.66–3.61 (m, 4H), 2.24–2.13 (m, 1H), 1.09–0.84 (m, 6H). 13 13C NMR (DMSO-d6, 100 MHz) δ = 173.8, 172.7, 167.3, 141.1, 133.2, 128.5, 128.2, 63.7, 59.0, 54.6, 52.1, 30.0, 19.6, 19.5. HRMS (ESI): Calcd for C 16 H 20 NO6 - [M-H] - 322.1296, found 322.1293.

[0175]

[0176] Product 2y, property: white solid;

[0177] 1 1H NMR (CDCl3, 400 MHz) δ = 7.56 (d, J = 7.3 Hz, 2H), 7.26–7.19 (m, 4H), 7.14–7.09 (m, 3H), 5.06–5.01 (m, 1H), 4.05–3.98 (s, 1H), 3.82–3.73 (m, 5H), 3.33–3.13 (m, 2H). 13 13C NMR (CDCl3, 100 MHz) δ = 175.3, 172.7, 167.6, 139.7, 139.6, 135.9, 132.6, 129.2, 128.7, 128.5, 127.6, 127.2, 63.9, 53.9, 53.5, 52.6, 37.7. HRMS (ESI): Calcd for C 10 H 20 NO6 - [M-H] - 370.1296, found 370.1292.

[0178]

[0179] Product 2z, property: white solid;

[0180] 1 1H NMR (DMSO-d6, 400 MHz) δ = 8.58 (d, J = 7.7 Hz, 1H), 7.84 (d, J = 7.7 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H), 4.36 (t, J = 7.6 Hz, 1H), 3.95 (t, J = 8.6 Hz, 1H), 3.74 (t, J = 6.0 Hz, 1H), 3.65–3.61 (m, 4H), 2.00–1.96 (m, 1H), 1.54–1.46 (m, 1H), 1.31–1.24 (m, 1H), 0.91–0.85 (m, 6H). 13 13C NMR (DMSO-d6, 100 MHz) δ = 173.8, 172.7, 167.2, 141.1, 133.2, 128.5, 128.2, 63.7, 57.8, 54.6, 52.2, 36.1, 25.7, 16.0, 11.3. HRMS (ESI): Calcd for C 12 H 22 NO6 - [M-H] - 336.1453, found 336.1451.

[0181]

[0182] Product 3a, property: colorless liquid;

[0183] 1 H NMR(CDCl3,400MHz)δ=7.28–7.19(m,5H),3.74(t,J=10.7Hz,1H),3.59(s,3H),3.52–3.48(m,1H),2.34–2.26(m,1H),1.98–1.89(m,1H),1.64(s,1H). 13 C NMR(CDCl3,100MHz)δ=174.6,138.7,128.8,128.0,127.4,60.5,52.1,48.0,36.1.HRMS(ESI):Calcdfor C 11 H 14 NaO3 + [M+Na] + 217.0835,found 217.0834.

[0184]

[0185] Product 3b, property: white solid;

[0186] 1 H NMR(CDCl3,400MHz)δ=7.32–7.22(m,10H),3.68(s,3H),3.57(t,J=6.4Hz,2H),2.47–2.42(m,2H),1.53(s,1H),1.36–1.29(m,2H). 13 C NMR(CDCl3,100MHz)δ=174.9,142.8,128.9,127.9,126.8,63.0,60.1,52.4,34.4,28.7.HRMS(ESI):Calcd for C 18 H 21 O3 + [M+H] + 285.1485,found 285.1480.

[0187]

[0188] Product 3c, property: white solid;

[0189] 11H NMR (CDCl3, 400 MHz) δ = 7.31–7.22 (m, 10H), 3.67 (s, 3H), 3.55 (t, J = 6.6 Hz, 2H), 2.40–2.36 (m, 2H), 1.64 (s, 1H), 1.57–1.49 (m, 2H), 1.13–1.07 (m, 2H). 13 13C NMR (CDCl3, 100 MHz) δ = 175.0, 142.9, 128.9, 127.9, 126.8, 62.5, 60.4, 52.4, 37.8, 32.9, 21.5. HRMS (ESI): Calcd for C 19 H 23 O3 + [M + H] + 299.1642, found 299.1639.

[0190] The present invention has been described in detail above in combination with specific embodiments and exemplary examples. However, these descriptions should not be construed as limiting the present invention. Those skilled in the art understand that, without departing from the spirit and scope of the present invention, various equivalent substitutions, modifications or improvements can be made to the technical solutions and their implementation manners of the present invention, and all of these fall within the scope of the present invention. The protection scope of the present invention shall be subject to the appended claims.

Claims

1. A method for preparing β-hydroxy acids and / or β-hydroxy acid derivatives by electrocarboxylation of epoxides with carbon dioxide, characterized in that, It includes the following steps: In a CO2 atmosphere, after dissolving an epoxide and a supporting electrolyte in a solvent, an electrocarboxylation reaction occurs under the condition of energization, followed by acidification and optionally post-treatment to obtain the β-hydroxy acid and / or β-hydroxy acid derivative; When conducting the energized reaction, among the electrodes used, the cathode material is selected from graphite felt and platinum sheet; the anode material is selected from magnesium sheet, zinc sheet, and aluminum sheet; The solvent is selected from at least one of amide solvents and nitrile solvents; The supporting electrolyte is selected from at least one of halogen salts; The epoxide has the following general structural formula: Said Ar is selected from unsubstituted aromatic groups; R 1 , R 2 , R 3 Each is independently selected from hydrogen, C1-C5 alkyl, phenyl; R 4 selected from hydrogen, alkyl, halogen atom, nitro, cyano, aryl; The n is any integer selected from 1 to 4; The carbon atoms forming the ring on the oxygen-containing ring in the epoxide are single carbon-carbon bonds; Alternatively, the epoxide includes the following compounds:

2. The method according to claim 1, wherein: The n is 1; the epoxide has the following general structural formula: At least one of R2 and R3 is selected from hydrogen; R 4 selected from hydrogen, alkyl, halogen atom, nitro group, cyano group, aryl group; The carbon atoms forming the ring on the oxygen-containing ring in the epoxide are single carbon-carbon bonds.

3. The method according to claim 2, wherein: The epoxide of the general structural formula 2 includes the following compounds:

4. The method according to claim 1, wherein: The n is 2-4; the epoxide has the following general structural formula: Said R 1 is selected from hydrogen and unsubstituted phenyl.

5. The method according to claim 4, wherein: The epoxide of the general structural formula 3 includes the following compounds:

6. The method according to claim 1, wherein: The molar equivalent of the supporting electrolyte is 50%-100% of the epoxide; The halogen salt is selected from at least one of tetraalkylhalogen salts or inorganic halogen salts.

7. The method according to claim 6, wherein: The tetraalkylhalogen salt is selected from at least one of tetraethylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, and tetrabutylammonium tetrafluoroborate; The inorganic halogen salt is selected from at least one of sodium iodide, potassium iodide, and ammonium iodide.

8. The method according to claim 1, wherein: The concentration of the epoxide in the solvent is 0.05-0.4 mol / L; The solvent is selected from at least one of N,N-dimethylformamide, N,N-dimethylacetamide, and acetonitrile.

9. The method according to claim 8, wherein: The concentration of the epoxide in the solvent is 0.1-0.2 mol / L.

10. The method according to claim 1, wherein: When conducting the energized reaction, a constant current is passed; When acidifying, the concentration of the acid used is 1-2 mol / L, and / or, The post-treatment includes directly extracting and concentrating to obtain a crude product; the step of purifying the obtained crude product; or the post-treatment includes directly extracting and concentrating to obtain a crude product; performing an esterification reaction on the obtained crude product, preparing it into a methyl carboxylate and then performing purification.

11. The method according to claim 10, wherein: The constant current is 1-30 mA; and / or, The energized reaction time is 0.5-20 h; and / or, The energized reaction temperature is -20-50 °C; and / or, When acidifying, the acid used is hydrochloric acid; and / or, The purification method is column chromatography.

12. The method according to claim 11, characterized in that: the constant current is 5-15 mA; and / or, the energized reaction time is 3.5-14 h; and / or, the energized reaction temperature is -10-30 °C.

13. Use of the method according to any one of claims 1-12 in constructing a drug molecule containing β-hydroxy acid and / or β-hydroxy acid derivative.

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