Electrochemical synthesis method and application of prolinol compound

Abstract

The invention discloses an electrochemical synthesis method and application of a prolinol compound, and belongs to the technical field of synthesis of organic compounds, the electrochemical synthesis method comprises the following steps: taking a benzyl-containing compound as a substrate, adding the substrate, a metal catalyst, an iodine source additive and an electrolyte into an organic solvent, and carrying out electrochemical reaction, separation and purification to obtain the prolinol compound. The prolinol compound is obtained. By matching the specific substrate, the metal catalyst and the oxide, the yield of the prolinol compound is increased, and the preparation method is simple, economical and environmentally friendly. The prolinol derivative is suitable for preparing the prolinol derivative-based antitumor drug.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis technology, and relates to an electrochemical synthesis method and application of proline alcohol compounds. Background Technology

[0002] Proline derivatives have significant applications in the pharmaceutical field due to their broad range of biological activities. Studies have shown that these compounds can effectively induce tumor cell apoptosis through mechanisms such as inhibiting the expression of tumor-related proteins, exhibiting good anti-tumor activity. Furthermore, they possess various pharmacological effects, including antibacterial, antioxidant, analgesic, and neuroprotective properties. Therefore, the efficient synthesis of proline compounds is of great importance for developing novel drugs and expanding disease treatment options.

[0003] Currently, several synthetic methods have been reported for the preparation of proline alcohols. For example, in 2013, Yu Lei's research group proposed using proline as a raw material, employing solid phosgene as an aminocarboxyl protecting agent, and hydrolyzing the product after reaction with a Grignard reagent in tetrahydrofuran solvent. In 2019, Liu Guosheng's research group reported a palladium-catalyzed non-activated olefin aminofluorination reaction, which can be used for the efficient synthesis of enantiomeric fluoropiperidine compounds (see Angew. Chem. Int. Ed. 2019, 131, 1–6). Subsequently, Shi Bingfeng's research group developed a cobalt-catalyzed system using pyridinecarboxamide as a directing group to achieve highly enantioselective synthesis of DAMA derivatives (see Angew. Chem. Int. Ed. 2023, 62, e202304706).

[0004] However, the existing synthetic methods mentioned above still have room for improvement: First, the reaction steps are usually quite complicated, involving multiple protection and deprotection operations, resulting in low synthesis efficiency; second, some methods use highly toxic reagents such as solid phosgene or precious metal catalysts such as palladium, which are not only environmentally unfriendly but also pose potential safety risks and post-processing challenges; in addition, these methods usually require expensive catalysts or special ligands, resulting in high synthesis costs and limiting their application on an industrial scale.

[0005] Therefore, given the shortcomings of existing synthetic methods in terms of step complexity, environmental friendliness, and economy, there is an urgent need to develop a new synthetic method for proline alcohols that is simple, efficient, environmentally friendly, and cost-effective, in order to meet the pressing demand for green and sustainable synthetic routes in drug development and related fields. Summary of the Invention

[0006] In view of the above-mentioned shortcomings of the prior art, the purpose of this invention is to provide an electrochemical synthesis method for proline alcohol compounds, so as to achieve a simple, efficient, environmentally friendly and cost-effective preparation of proline alcohol compounds through electrolysis.

[0007] Another object of the present invention is to provide the application of the above preparation method in the preparation of antitumor drugs based on proline alcohol derivatives.

[0008] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0009] An electrochemical synthesis method for proline alcohols involves carrying out an electrochemical reaction of a benzyl compound, an electrolyte, a catalyst, and an iodine source additive in an organic solvent to obtain proline alcohols.

[0010] The structural formula (I) of the benzyl-containing compound is:

[0011]

[0012] The structural formula (II) of the proline alcohol compound is:

[0013]

[0014] Among them, R 1 -Ph, cyclohexyl, or -H; R 2 -H;

[0015] R 3 For -H, -F, -Br, -CH3, -NO2, i-Pr, or OMe;

[0016] R 4 =OEt, OMe, or n-Pr;

[0017] The molar ratio of the benzyl compound, electrolyte, catalyst, and iodine source additive is 2-4:3.75:1-3:2-4;

[0018] The concentration of the benzyl-containing compound in the organic solvent is not less than 0.0166 mol / L.

[0019] As a limitation of the present invention, the electrochemical reaction is carried out by electrolysis with a constant current.

[0020] The constant current is 10-20mA, preferably 15mA.

[0021] The electrochemical reaction takes 3 to 5 hours and is carried out at a temperature of -10 to 10°C.

[0022] As another limitation of the present invention, the anode electrode used in electrolysis is a carbon electrode, and the cathode electrode is a platinum sheet electrode.

[0023] As a further limitation of the present invention, the electrolyte is tetrabutylammonium hexafluorophosphate, i.e., nBu4NPF6.

[0024] As a further limitation of the present invention, the catalyst is a metal Salen complex.

[0025] Furthermore, the metal Salen complex (Salen M) is any one of the following:

[0026]

[0027] The aforementioned metal Salen complexes are labeled P1 to P8 in sequence.

[0028] As a further limitation of the present invention, the iodine source additive is iodobenzene, i.e., PhI.

[0029] Furthermore, the iodine source additive may also be 3,4-dimethoxyiodobenzene, sodium iodide, or m-bromoiodobenzene.

[0030] As a further limitation of the present invention, the organic solvent is a mixed solvent made of acetonitrile and ethanol in a volume ratio of 1 to 10:1.

[0031] As a further limitation of the present invention, after the electrochemical reaction is completed, the reaction solution is used to remove the organic solvent residue using a rotary evaporator, and after separation and purification, the proline alcohol compound is obtained.

[0032] The reaction solution refers to all the liquids in the diaphragmless electrolytic cell at the end of the reaction.

[0033] As a further limitation of the present invention, the separation and purification are performed using silica gel column chromatography.

[0034] The eluent is a mixture of petroleum ether and ethyl acetate in a ratio of 200 to 400:1.

[0035] The present invention also provides an application of an electrochemical synthesis method for proline alcohol compounds, specifically for the preparation of antitumor drugs based on proline alcohol compounds.

[0036] The reaction route of this invention is as follows:

[0037]

[0038] By adopting the above technical solution, the technical progress achieved by this invention compared with the prior art is as follows:

[0039] The electrochemical synthesis method of proline alcohols of the present invention uses a benzyl-containing compound with a specific structure as a substrate, iodobenzene as an additive, Salen M as a catalyst, and tetrabutylammonium hexafluorophosphate as an electrolyte. Proline alcohols are prepared by electrolysis in an organic solution under constant current. The reaction route is short and the preparation efficiency is improved.

[0040] The electrochemical synthesis method for proline alcohols of the present invention can directly synthesize the target product in a one-step reaction, which significantly simplifies the cumbersome multi-step reaction process in traditional processes and thus greatly improves the synthesis efficiency. Through extensive experimental analysis, specific substrate structures were determined and specific Salen M catalysts and iodine source additives were matched, eliminating highly toxic reagents and precious metal catalysts and making the reaction conditions more environmentally friendly. At the same time, its core feature of reusable electrodes effectively reduces the cost of raw materials and consumables, which is conducive to industrial-scale application.

[0041] The electrochemical synthesis method for proline alcohol compounds of the present invention has mild process conditions and high operational safety, and is suitable for the preparation of antitumor drugs based on proline alcohol derivatives. Attached Figure Description

[0042] Figure 1 The proline alcohol compounds prepared in Example 1 of this invention 1 H NMR spectrum;

[0043] Figure 2 The proline alcohol compounds prepared in Example 1 of this invention 13 C NMR spectrum;

[0044] Figure 3 The proline alcohol compounds prepared in Example 2 of this invention 1 H NMR spectrum;

[0045] Figure 4 The proline alcohol compounds prepared in Example 2 of this invention 13 C NMR spectrum;

[0046] Figure 5 The proline alcohol compounds prepared in Example 3 of this invention 1 H NMR spectrum;

[0047] Figure 6 The proline alcohol compounds prepared in Example 3 of this invention 13 C NMR spectrum;

[0048] Figure 7 The proline alcohol compounds prepared in Example 4 of this invention 1 H NMR spectrum;

[0049] Figure 8 The proline alcohol compounds prepared in Example 4 of this invention 13 C NMR spectrum;

[0050] Figure 9 The proline alcohol compounds prepared in Example 5 of this invention 1 H NMR spectrum;

[0051] Figure 10 The proline alcohol compounds prepared in Example 5 of this invention 13 C NMR spectrum;

[0052] Figure 11 The proline alcohol compounds prepared in Example 6 of this invention 1 H NMR spectrum;

[0053] Figure 12 The proline alcohol compounds prepared in Example 6 of this invention 13 C NMR spectrum;

[0054] Figure 13 The proline alcohol compounds prepared in Example 7 of this invention 1 H NMR spectrum;

[0055] Figure 14 The proline alcohol compounds prepared in Example 7 of this invention 13 C NMR spectrum;

[0056] Figure 15 The proline alcohol compounds prepared in Example 8 of this invention 1 H NMR spectrum;

[0057] Figure 16 The proline alcohol compounds prepared in Example 8 of this invention 13 C NMR spectrum. Detailed Implementation

[0058] The present invention will be further described in detail below through specific embodiments. It should be understood that the described embodiments are only for explaining the present invention and do not limit the present invention.

[0059] Unless otherwise specified, the experimental methods used in the following examples are conventional methods in the art. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0060] Example 1

[0061] This embodiment describes an electrochemical synthesis method for proline alcohol compounds. Specifically, the following steps are taken: In an electrolytic cell, the substrate N-benzyl-5-methyl-2,2-diphenylhex-4-en-1-amine (0.25 mmol), catalyst Salen M (0.1 mmol), iodine source additive iodobenzene (0.375 mmol), tetrabutylammonium hexafluorophosphate (0.25 mmol), acetonitrile (12 mL), and ethanol (4 mL) are added sequentially. The mixture is stirred at -10°C until homogeneous, and this temperature is maintained as the reaction temperature. A carbon rod is used as the anode, and a platinum sheet is used as the cathode. Electrodes are inserted, the power supply is turned on, and the constant current is adjusted to 10 mA. The electrolysis reaction is carried out for 4 hours. After the reaction was complete, the organic solvent was removed by rotary evaporation. The residue was purified by rapid silica gel column chromatography using petroleum ether:ethyl acetate at a ratio of 250:1. The eluent yielded a pale yellow oily liquid product, which was a proline alcohol compound. Analysis showed that its structure was 1-benzyl-2-(2-ethoxypropyl-2-yl)-4,4-diphenylpyrrolidine.

[0062] When the catalyst was Salen Mn(Cl) [cyclohexyl], the yield was 75%.

[0063] When the catalyst was Salen Mn(Cl) [diphenyl], the yield was 67%.

[0064] When the catalyst is Salen Cu [cyclohexyl], the yield is 80%.

[0065] When the catalyst is Salen Cu [diphenyl], the yield is 70%;

[0066] When the catalyst is Salen Co [cyclohexyl], the yield is 60%;

[0067] When the catalyst was Salen Co [diphenyl], the yield was 57%.

[0068] When the catalyst is Salen Ni [cyclohexyl], the yield is 65%;

[0069] When the catalyst is Salen Ni (diphenyl), the yield is 73%.

[0070] The structural formula of the obtained proline alcohol compounds is as follows:

[0071]

[0072] The proline NMR spectra of the obtained proline compounds were obtained, such as... Figure 1 The hydrogen NMR characterization data are as follows:

[0073] 1H NMR (400MHz, CDCl3) δ7.35–7.09(m,15H),4.27(d,J=13.7Hz,1H),3.52(d,J=11.0Hz,1H),3. 45–3.23(m,2H),3.19–3.05(m,3H),2.95–2.89(m,1H),2.13–2.05(m,1H),1.11–1.02(m,9H).

[0074] The carbon NMR spectra of the obtained proline compounds were detected, such as... Figure 2 The carbon NMR characterization data are as follows: 13 C NMR (101MHz, CDCl3) δ149.3,147.6,141.7,135.9,130.1,129.2,128.3,128.3,128.2,128.0,127.8,127.3,1 27.1,126.6,126.0,125.6,78.7,70.7,65.1,61.1,56.4,53.2,41.6,22.6,21.4,16.3.HRMS(ESI)calculated for C 28 H 34 NO[M+H]+:400.2640,found:400.2641.

[0075] Comparative Examples 1-4

[0076] The only difference between Comparative Examples 1-4 and Example 1 is the iodine source additive. Specifically, sodium periodate, 3,4-dimethoxyiodobenzene, sodium iodide, and m-bromoiodobenzene were used as the iodine source additive, respectively. All other preparation steps were the same. The results showed that:

[0077] Comparative Example 1 used sodium periodate as an iodine source additive, and the target product was not detected.

[0078] Comparative Example 2 used 3,4-dimethoxyiodobenzene as the iodine source additive and different metal Salen complexes as catalysts, and the yield of the product was 35-75%.

[0079] Comparative Example 3 used sodium iodide as the iodine source additive and different metal Salen complexes as catalysts, and the yield of the obtained product was 30-50%.

[0080] Comparative Example 4 used m-bromoiodobenzene as the iodine source additive and different metal Salen complexes as catalysts, and the yield of the product was 15-30%.

[0081] Comparative Examples 5-6

[0082] The only difference between Comparative Examples 5 and 6 and Example 1 is the reaction temperature, specifically 10°C or 0°C. The other preparation steps are the same. The results show that the yields of proline alcohols obtained by using different metal Salen complexes as catalysts are 30-40% and 25-35%, respectively.

[0083] Example 2

[0084] The difference between this embodiment and Example 1 is that the substrate is replaced with an equal amount of N-(4-fluorobenzyl)-5-methyl-2,2-diphenylhex-4-en-1-amine, and the catalyst is P1. The other preparation steps are the same. The resulting proline alcohol compound is 2-(2-ethoxypropane-2-yl)-1-(4-fluorobenzyl)-4,4-diphenylpyrrolidine, with the following structural formula:

[0085]

[0086] The proline NMR spectra of the obtained proline compounds were obtained, such as... Figure 3 The hydrogen NMR characterization data are as follows: 1 H NMR (400MHz, CDCl3) δ7.25–7.17(m,6H),7.15–7.02(m,6H),6.91(t,J=8.7Hz,2H),4.20(d,J=13.5Hz,1H),3.49(d,J=10.9Hz ,1H),3.41–3.32(m,2H),3.11–3.04(m,2H),3.00(d,J=10.9Hz,1H),2.95–2.85(m,1H),2.17–2.07(m,1H),1.14–1.04(m,9H).

[0087] The carbon NMR spectra of the obtained proline compounds were detected, such as... Figure 4 The carbon NMR characterization data are as follows: 13 C NMR(101MHz, CDCl3)δ161.6(d,JC–F=243.8Hz),149.1,147.4,137.2(d,JC–F=2.9Hz),129.6(d,JC–F=7.7Hz),128.3,1 28.0,127.2,127.0,125.8(d,JC–F=42.6Hz),114.9,114.7,78.6,70.5,64.9,60.1,56.3,53.0,41.5,22.5,21.1,16.2.

[0088] In various implementation methods, by using different catalysts, the product yield is 60-80%.

[0089] Example 3

[0090] The difference between this example and Example 1 is that the substrate is replaced with an equal amount of N-(4-bromobenzyl)-5-methyl-2,2-diphenylhex-4-en-1-amine, and the catalyst is P2. The other preparation steps are the same. The resulting proline alcohol compound is 1-(4-bromobenzyl)-2-(2-ethoxypropyl-2-yl)-4,4-diphenylpyrrolidine, with the following structural formula:

[0091]

[0092] The proline NMR spectra of the obtained proline compounds were obtained, such as... Figure 5 The hydrogen NMR characterization data are as follows: 1 H NMR (400MHz, CDCl3) δ7.31(d,J=7.3Hz,2H),7.20–6.98(m,12H),4.17(d,J=13.9Hz,1H),3.48(d,J=10.9Hz,1H),3.32–3.19(m,2H),3 .05(t,J=10.2Hz,2H),2.98(d,J=11.1Hz,1H),2.88–2.79(m,1H),2.05–1.91(m=1H),1.11(s,3H),1.10(s,3H),1.07(t,J=6.9Hz,3H).

[0093] The carbon NMR spectra of the obtained proline compounds were detected, such as... Figure 6 The carbon NMR characterization data are as follows: 13 C NMR (101MHz, CDCl3) δ148.0,146.4,139.7,130.2,128.9,128.2,127.3,127.2,127.0,126.7,1 26.2,126.0,125.0,124.6,119.1,77.7,69.7,64.1,59.4,55.3,52.1,40.4,21.5,20.0,15.2.

[0094] In various implementation methods, by using different catalysts, the product yield is 68-83%.

[0095] Example 4

[0096] The difference between this example and Example 1 is that the substrate is replaced with an equal amount of 5-methyl-N-(4-nitrobenzyl)-2,2-diphenylhex-4-en-1-amine, and the catalyst is P3. The other preparation steps are the same. The resulting proline alcohol compound is 2-(2-ethoxypropyl-2-yl)-1-(4-nitrobenzyl)-4,4-diphenylpyrrolidine, with the following structural formula:

[0097]

[0098] The proline NMR spectra of the obtained proline compounds were obtained, such as... Figure 7 The hydrogen NMR characterization data are as follows: 1 H NMR (400MHz, CDCl3) δ8.05–8.03(d,J=8.7Hz,2H),7.36(d,J=8.4Hz,2H),7.25(d, J=7.1Hz,1H),7.21–7.15(m,4H),7.08–7.03(m,4H),6.98(d,J=9.3Hz,1H),4.28(d ,J=14.9Hz,1H),3.51(d,J=10.9Hz,1H),3.35–3.22(m,3H),3.13–3.05(m,1H),3.0 2(d,J=10.9Hz,1H),2.88(m,1H),2.05(m,1H),1.03(s,6H),0.94(t,J=6.9Hz,3H).

[0099] The carbon NMR spectra of the obtained proline compounds were detected, such as... Figure 8 The carbon NMR characterization data are as follows: 13 C NMR (101MHz, CDCl3) δ149.9,148.6,147.2,146.8,128.7,128.5,128.4,128.2,127.6,127.2,1 26.9,126.6,126.2,125.8,123.5,78.8,71.1,65.5,60.8,56.4,53.5,41.4,22.6,20.6,16.2.

[0100] In various implementation methods, by using different catalysts, the product yield is 70-80%.

[0101] Example 5

[0102] The difference between this example and Example 1 is that the substrate is replaced with an equal amount of 5-methyl-N-(4-methylbenzyl)-2,2-diphenylhex-4-en-1-amine, and the catalyst is P4. The other preparation steps are the same, and the resulting proline compound is 2-(2-ethoxypropyl-2-yl)-1-(4-methylbenzyl)-4,4-diphenylpyrrolidine, with the following structural formula:

[0103]

[0104] The proline NMR spectra of the obtained proline compounds were obtained, such as... Figure 9 The hydrogen NMR characterization data are as follows: 1H NMR (400MHz, CDCl3) δ7.23–7.03(m,14H),4.22(d,J=13.4Hz,1H),3.51(d,J=11.0Hz,1H),3.38–3.1 1(m,2H),3.06–2.99(m,3H),2.95–2.88(m,1H),2.26(s,3H),2.08–1.96(m,1H),1.17–1.06(m,9H).

[0105] The carbon NMR spectra of the obtained proline compounds were detected, such as... Figure 10 The carbon NMR characterization data are as follows: 13 C NMR (101MHz, CDCl3) δ148.2,146.5,137.5,134.9,129.0,127.8,127.2,126.9,126.2, 126.1,124.9,124.4,77.6,69.5,63.9,59.6,55.3,52.0,40.5,21.5,20.4,20.1,15.2.

[0106] In various implementation methods, by using different catalysts, the product yield is 73-83%.

[0107] Example 6

[0108] The difference between this example and Example 1 is that the substrate is replaced with an equal amount of N-(4-methoxybenzyl)-5-methyl-2,2-diphenylhex-4-en-1-amine, and the catalyst is P5. The other preparation steps are the same. The resulting proline alcohol compound is 2-(2-ethoxypropyl-2-yl)-1-(4-methoxybenzyl)-4,4-diphenylpyrrolidine, with the following structural formula:

[0109]

[0110] The proline NMR spectra of the obtained proline compounds were obtained, such as... Figure 11 The hydrogen NMR characterization data are as follows: 1 H NMR (400MHz, CDCl3) δ7.23–7.05(m,12H),6.78(d,J=8.1Hz,2H),4.17(d,J=13.3Hz,1H),3.71(s,3H),3.49(d, J=10.9Hz,1H),3.37–3.22(m,2H),3.02–2.96(m,3H),2.92–2.83(m,1H),2.11–2.02(m,1H),1.09–1.01(m,9H).

[0111] The carbon NMR spectra of the obtained proline compounds were detected, such as... Figure 12 The carbon NMR characterization data are as follows: 13 C NMR (101MHz, CDCl3) δ158.4,149.4,147.7,129.5,128.6,128.3,128.1,127.4,127.2, 126.0,125.6,113.6,78.7,70.6,64.9,60.3,56.4,55.3,53.1,41.6,22.6,21.5,16.3.

[0112] In various implementation methods, by using different catalysts, the product yield is 58-79%.

[0113] Example 7

[0114] The difference between this embodiment and Example 1 is that the substrate is replaced with an equal amount of N-benzyl-1-[1-(3-methylbut-2-en-1-yl)cyclohexyl]methylamine, the catalyst is P6, and the other preparation steps are the same. The resulting proline alcohol compound is 2-benzyl-3-(2-ethoxypropyl-2-yl)-2-azaspiro[4.5]decane, with the following structural formula:

[0115]

[0116] The proline NMR spectra of the obtained proline compounds were obtained, such as... Figure 13 The hydrogen NMR characterization data are as follows: 1 H NMR (400MHz, CDCl3) δ7.29–7.02(m,5H),4.60(d,J=13.8Hz,1H),3.45–3.37(m,1H),3.34–3.30(m,1H),3.12(d,J=13.9Hz,1H), 2.78(t,J=8.7Hz,1H),2.67(d,J=9.7Hz,1H),1.88(d,J=9.7Hz,1H),1.58–1.51(m,1H),1.32–1.19(m,14H),1.06–1.01(m,6H).

[0117] The carbon NMR spectra of the obtained proline compounds were detected, such as... Figure 14 The carbon NMR characterization data are as follows: 13 C NMR (101MHz, CDCl3) δ141.9,128.1,128.1,126.2,78.5,69.1,60.5,56.1,39.4,38.4,38.0,26.2,23.6,23.4,20.4,16.2.

[0118] Example 8

[0119] The difference between this embodiment and Example 1 is that the substrate is replaced with an equal amount of N-benzyl-2,2,5-trimethylhex-4-en-1-amine, and the catalyst is P7. The other preparation steps are the same, and the resulting proline alcohol compound is 1-benzyl-2-(2-ethoxypropyl-2-yl)-4,4-dimethylpyrrolidine, with the following structural formula:

[0120]

[0121] The proline NMR spectra of the obtained proline compounds were obtained, such as... Figure 15 The hydrogen NMR characterization data are as follows: 1 H NMR (400MHz, CDCl3) δ7.29–7.11(m,5H),4.57(d,J=13.8Hz,1H),3.45–3.36(m,2H),3.21–3.16(d,J=13.8Hz,1H),2.89–2.83(m,1 H),2.57(d,J=9.6Hz,1H),1.94(d,J=9.6Hz,1H),1.57–1.51(m,1H),1.25–1.18(m,4H),1.05–1.01(m,6H),0.93(t,J=7.2Hz,6H).

[0122] The carbon NMR spectra of the obtained proline compounds were detected, such as... Figure 16 The carbon NMR characterization data are as follows: 13 C NMR (101MHz, CDCl3) δ141.9,128.1,128.0,126.2,78.5,70.2,68.6,60.7,56.1,43.9,35.7,29.7,29.4,28.7,23.2,20.5,16.2.

[0123] In various implementation methods, by using different catalysts, the product yield is 50-56%.

[0124] Examples 9-25

[0125] Examples 9-25 are electrochemical synthesis methods for proline alcohol compounds. The specific methods are basically the same as those in Example 1, except that the substrate is replaced with a benzyl compound with the structural formula (I) (the amount of substance is the same as in Example 1), the catalyst is P8, and the types of organic solvents are different (the total amount is the same as in Example 1). The proline alcohol compounds obtained in each example are shown in Table 1.

[0126] Table 1. Proline compounds prepared in Examples 9-25

[0127]

[0128]

[0129] The NMR characterization results of product 2a were as follows: ¹H NMR (400MHz, CDCl₃) δ 7.35–7.09 (m, 15H), 4.27 (d, J = 13.7Hz, 1H), 3.52 (d, J = 11.0Hz, 1H), 3.45–3.23 (m, 2H), 3.19–3.05 (m, 3H), 2.95–2.89 (m, 1H), 2.13–2.05 (m, 1H), 1.11–1.02 (m, 9H). 13 C NMR (101MHz, CDCl3) δ149.3,147.6,141.7,135.9,130.1,129.2,128.3,128.3,128.2,128.0,127.8,127.3,1 27.1,126.6,126.0,125.6,78.7,70.7,65.1,61.1,56.4,53.2,41.6,22.6,21.4,16.3.HRMS(ESI)calculated for C 28 H 34 NO[M+H] + :400.2640,found:400.2641.

[0130] In various embodiments, by using different catalysts, the yield of product 2a is 65-85%.

[0131] The NMR characterization results of product 2b are as follows: 1 H NMR (400MHz, CDCl3) δ7.25–7.17(m,6H),7.15–7.02(m,6H),6.91(t,J=8.7Hz,2H),4.20(d,J=13.5Hz,1H),3.49(d,J=10.9Hz ,1H),3.41–3.32(m,2H),3.11–3.04(m,2H),3.00(d,J=10.9Hz,1H),2.95–2.85(m,1H),2.17–2.07(m,1H),1.14–1.04(m,9H). 13 C NMR(101MHz,CDCl3)δ161.6(d,J C–F =243.8Hz),149.1,147.4,137.2(d,J C–F =2.9Hz), 129.6(d,J C–F =7.7Hz),128.3,128.0,127.2,127.0,125.8(d,J C–F=42.6Hz),114.9,114.7,78.6,70.5,64.9,60.1,56.3,53.0,41.5,22.5,21.1,16.2. 19 F NMR(376MHz,CDCl3)δ-116.7.HRMS(ESI)calculated for C 28 H 33 FNO[M+H] + :418.2546,found:418.2541.

[0132] In various embodiments, by using different catalysts, the yield of product 2b is 60-80%.

[0133] The NMR characterization results of product 2c are as follows: 1 H NMR (400MHz, CDCl3) δ7.31(d,J=7.3Hz,2H),7.20–6.98(m,12H),4.17(d,J=13.9Hz,1H),3.48(d,J=10.9Hz,1H),3.32–3.19(m,2H),3 .05(t,J=10.2Hz,2H),2.98(d,J=11.1Hz,1H),2.88–2.79(m,1H),2.05–1.91(m=1H),1.11(s,3H),1.10(s,3H),1.07(t,J=6.9Hz,3H). 13 C NMR (101MHz, CDCl3) δ148.0,146.4,139.7,130.2,128.9,128.2,127.3,127.2,127.0,126.7,126.2,126. 0,125.0,124.6,119.1,77.7,69.7,64.1,59.4,55.3,52.1,40.4,21.5,20.0,15.2.HRMS(ESI)calculated forC 28 H 33 BrNO[M+H] + :478.1746,found:478.1749.

[0134] In various embodiments, by using different catalysts, the yield of product 2c is 68-83%.

[0135] The NMR characterization results of the product 2d are as follows: 1H NMR (400MHz, CDCl3) δ8.05–8.03(d,J=8.7Hz,2H),7.36(d,J=8.4Hz,2H),7.25(d, J=7.1Hz,1H),7.21–7.15(m,4H),7.08–7.03(m,4H),6.98(d,J=9.3Hz,1H),4.28(d ,J=14.9Hz,1H),3.51(d,J=10.9Hz,1H),3.35–3.22(m,3H),3.13–3.05(m,1H),3.0 2(d,J=10.9Hz,1H),2.88(m,1H),2.05(m,1H),1.03(s,6H),0.94(t,J=6.9Hz,3H). 13 C NMR (101MHz, CDCl3) δ149.9,148.6,147.2,146.8,128.7,128.5,128.4,128.2,127.6,127.2,126.9,126. 6,126.2,125.8,123.5,78.8,71.1,65.5,60.8,56.4,53.5,41.4,22.6,20.6,16.2.HRMS(ESI)calculated for C 28 H 33 N₂O₃[M+H] + :445.2491; found:445.2492.

[0136] In various embodiments, by using different catalysts, the yield of product 2d is 70-80%.

[0137] The NMR characterization results of product 2e are as follows: 1 H NMR (400MHz, CDCl3) δ7.23–7.03(m,14H),4.22(d,J=13.4Hz,1H),3.51(d,J=11.0Hz,1H),3.38–3.1 1(m,2H),3.06–2.99(m,3H),2.95–2.88(m,1H),2.26(s,3H),2.08–1.96(m,1H),1.17–1.06(m,9H). 13C NMR (101MHz, CDCl3) δ148.2,146.5,137.5,134.9,129.0,127.8,127.2,126.9,126.2,126.1,124. 9,124.4,77.6,69.5,63.9,59.6,55.3,52.0,40.5,21.5,20.4,20.1,15.2.HRMS(ESI)calculated for C 29 H 36 NO[M+H] + :414.2797,found:414.2796.

[0138] In various implementation methods, by using different catalysts, the yield of product 2e is 73-83%.

[0139] The NMR characterization results of product 2f are as follows: 1 H NMR (400MHz, CDCl3) δ7.33–7.06(m,14H),4.28(d,J=13.6Hz,1H),3.60(d,J=11.0Hz,1H),3.53–3.41(m,2H),3.15(t,J=10.1Hz,3 H),3.03–2.96(m,1H),2.94–2.86(m,1H),2.21–2.09(m,1H),1.26(d,J=6.8Hz,6H),1.16(d,J=14.7Hz,6H),1.11(t,J=6.8Hz,3H). 13 C NMR (101MHz, CDCl3) δ149.3,147.5,147.0,138.9,128.2,128.2,128.0,127.3,127.1,126.1,125.9,125 .5,78.6,70.6,65.0,60.7,56.3,53.2,41.5,33.7,24.1,24.1,22.5,21.5,16.2.HRMS(ESI)calculated for C 31 H 40 NO[M+H] + :442.3110,found:442.3112.

[0140] In various embodiments, by using different catalysts, the yield of product 2f is 60-75%.

[0141] The NMR characterization results of 2g of product are as follows: 1H NMR (400MHz, CDCl3) δ7.23–7.05(m,12H),6.78(d,J=8.1Hz,2H),4.17(d,J=13.3Hz,1H),3.71(s,3H),3.49(d, J=10.9Hz,1H),3.37–3.22(m,2H),3.02–2.96(m,3H),2.92–2.83(m,1H),2.11–2.02(m,1H),1.09–1.01(m,9H). 13 C NMR (101MHz, CDCl3) δ158.4,149.4,147.7,129.5,128.6,128.3,128.1,127.4,127.2,126.0,125. 6,113.6,78.7,70.6,64.9,60.3,56.4,55.3,53.1,41.6,22.6,21.5,16.3.HRMS(ESI)calculated for C 29 H 36 NO2[M+H] + :430.2746,found:430.2748.

[0142] In various embodiments, by using different catalysts, the yield of 2g of product was 58-79%.

[0143] The NMR characterization results of product 2j are as follows: 1 H NMR (400MHz, CDCl3) δ7.29–7.11(m,5H),4.57(d,J=13.8Hz,1H),3.45–3.36(m,2H),3.21–3.16(d,J=13.8Hz,1H),2.89–2.83(m,1 H),2.57(d,J=9.6Hz,1H),1.94(d,J=9.6Hz,1H),1.57–1.51(m,1H),1.25–1.18(m,4H),1.05–1.01(m,6H),0.93(t,J=7.2Hz,6H). 13 C NMR(101MHz, CDCl3)δ141.9,128.1,128.0,126.2,78.5,70.2,68.6,60.7,56.1,43.9,35.7,29.7,29.4,28.7,23.2,20.5,16.2.HRMS(ESI)calculated for C 18 H 30 NO[M+H] + :276.2327,found:276.2328.

[0144] In various embodiments, by using different catalysts, the yield of product 2j is 50-56%.

[0145] The NMR characterization results of product 3a are as follows: ¹H NMR (400MHz, CDCl₃) δ 7.23–6.98 (m, 15H), 4.19 (d, J = 13Hz, 1H), 3.52 (d, J = 11.0Hz, 1H), 3.13 (s, 3H), 3.15–3.01 (m, 3H), 2.93 (m, 1H), 2.10 (m, 1H), 1.09–1.05 (s, 6H). 13 C NMR (101MHz, CDCl3) δ149.1,147.4,141.5,128.2,128.2128.1,128.0,127.2,127.0,126.5 ,125.9,125.5,78.8,70.6,65.0,61.1,53.2,49.0,41.4,21.6,21.1.HRMS(ESI)calculated for C 27 H 32 NO[M+H] + :386.2484,found:386.2485.

[0146] In various embodiments, by using different catalysts, the yield of product 3a is 80-86%.

[0147] The NMR characterization results of product 3b are as follows: 1 H NMR (400MHz, CDCl3) δ7.26–7.15(m,6H),7.08(d,J=6.6Hz,5H),6.99(t,J=5.9Hz,1H),6.90(t,J=8.7Hz,2H),4.11(d,J=13.6 Hz,1H),3.49(d,J=11.0Hz,1H),3.13(s,3H),3.09–2.98(m,3H),2.97–2.89(m,1H),2.15–2.03(m,1H),1.05(d,J=7.3Hz,6H). 13 C NMR(101MHz,CDCl3)δ161.7(d,J C–F =243.8Hz),149.0,147.4,137.0(d,J C–F =2.9Hz), 129.6(d,J C–F =7.8Hz),128.3,128.0,127.2,127.0,125.8(d,J C–F=42.0Hz),115.0,114.8,78.8,70.5,64.8,60.3,53.1,49.0,41.3,21.6,20.9. 19 F NMR(376MHz,CDCl3)δ-116.6.HRMS(ESI)calculated for C 27 H 31 FNO[M+H] + :404.2390,found404.2389.

[0148] In various embodiments, by using different catalysts, the yield of product 3b is 73-85%.

[0149] The NMR characterization results of product 3c are as follows: ¹H NMR (400MHz, CDCl₃) δ 7.34 (d, J = 7.9Hz, 2H), 7.25–7.15 (m, 4H), 7.14–7.06 (m, 7H), 7.01 (d, J = 6.9Hz, 1H), 4.10 (d, J = 13.9Hz, 1H), 3.51 (d, J = 11.0Hz, 1H), 3.12 (s, 3H), 3.09–2.98 (m, 3H), 2.98–2.87 (m, 1H), 2.14–2.04 (m, 1H), 1.05 (d, J = 4.9Hz, 6H). 13 C NMR (101MHz, CDCl3) δ147.9,146.3,139.5,130.2,128.9,127.3,127.0,126.1,125.9,125. 0,124.6,119.1,77.8,69.5,63.959.4,52.2,48.0,40.2,20.6,19.8.HRMS(ESI)calculated for C 27 H 31 FNO[M+H] + :464.1589,found 464.1590.

[0150] In various implementation methods, by using different catalysts, the yield of product 3c is 68-78%.

[0151] The NMR characterization results of product 3e are as follows: ¹H NMR (400MHz, CDCl₃) δ 7.25–6.98 (m, 14H), 4.13 (d, J = 13.6Hz, 1H), 3.51 (d, J = 11.0Hz, 1H), 3.14 (s, 3H), 3.09–3.02 (m, 3H), 2.97–2.86 (m, 1H), 2.26 (s, 3H), 2.14–2.03 (m, 1H), 1.07 (d, J = 14.4Hz, 6H). 13 C NMR (101MHz, CDCl3) δ149.3,147.6,138.5,136.1,128.9,128.3,128.2,128.1,127.3,127.1,1 26.0,125.6,78.9,70.7,65.0,60.9,53.3,49.1,41.4,21.7,21.3,21.2.HRMS(ESI)calculated for C 28 H 34 NO[M+H] + :400.2640,found:400.2643.

[0152] In various embodiments, by using different catalysts, the yield of product 3e is 70-82%.

[0153] The NMR characterization results of product 3f are as follows: 1 H NMR (400MHz, CDCl3) δ7.37(d,J=9.0Hz,1H),7.27–7.10(m,12H),7.08–7.6.98(m,1H),4.12(d,J=13.7Hz,1H),3.53(d,J=11.1Hz,1H), 3.14(s,3H),3.10–3.03(m,3H),2.97–2.92(m,1H),2.86–2.79(m,1H),2.14–2.08(m,1H)1.26(d,J=6.9Hz,6H),1.16(d,J=15.0Hz,6H). 13 C NMR (101MHz, CDCl3) δ149.2,147.5,147.1,138.9,128.3,128.2,128.1,128.1,127.3,127.1,126.8,126.3,126.1, 126.0,125.6,118.5,78.9,70.7,65.0,60.9,53.4,49.2,41.3,33.8,24.2,24.2,21.6,21.3.HRMS(ESI)calculated for C 30 H38 NO[M+H] + :428.2953,found:428.2953.

[0154] In various implementation methods, by using different catalysts, the yield of product 3f was 70-79%.

[0155] The NMR characterization results of 3g of product are as follows: 1 H NMR (400MHz, CDCl3) δ7.27–6.95(m,12H),6.76(d,J=8.5Hz,2H),4.06(d,J=13.3Hz,1H),3.67(s,3H),3.48(d, J=11.0Hz,1H),3.11(s,3H),3.04–2.99(m,3H),2.95–2.90(m,1H),2.11–2.07(m,1H),1.05(d,J=13.6Hz,6H). 13 C NMR (101MHz, CDCl3) δ158.2,149.1,147.4,133.5,129.2,128.4,128.2,127.9,127.4,127.2,127.0,1 26.5,125.9125.4,78.8,76.0,70.4,64.6,60.3,53.1,49.0,41.2,21.5,21.2.HRMS(ESI)calculated for C 28 H 34 NO2[M+H] + :416.2590,found:416.2591.

[0156] In various implementation methods, by using different catalysts, the yield of product 3g was 65-79%.

[0157] The NMR characterization results of product 4a are as follows: ¹H NMR (400MHz, CDCl₃) δ 7.25–7.00 (m, 15H), 4.28 (d, J = 13.7Hz, 1H), 3.52 (d, J = 11.0Hz, 1H), 3.3–3.20 (m, 2H), 3.12–3.01 (m, 3H), 2.95–2.89 (m, 1H), 2.12–2.05 (m, 1H), 1.49–1.33 (m, 2H), 1.07 (d, J = 12.2Hz, 6H), 0.79 (t, J = 7.4Hz, 3H). 13C NMR (101MHz, CDCl3) δ149.3,147.7,141.7,128.4,128.3,128.2,128.1,127.4,127.2,126.5,126. 0,125.6,78.7,71.1,65.1,62.9,61.1,53.2,41.6,23.9,22.5,21.1,11.0.HRMS(ESI)calculated for C 29 H 36 NO[M+H] + :414.2797,found:414.2796.

[0158] In various embodiments, by using different catalysts, the yield of product 4a is 75-85%.

[0159] The NMR characterization results of product 4b are as follows: 1 H NMR (400MHz, CDCl3) δ7.22–6.90(m,14H),4.21(d,J=13.5Hz,1H),3.49(d,J=10.8Hz,1H),3.29–3.19(m,2H),3.07– 2.96(m,3H),2.95–2.88(m,1H),2.13(t,J=10.9Hz,1H),1.41(d,J=6.7Hz,2H),1.06(s,6H),0.79(t,J=8.0Hz,3H). 13 C NMR(101MHz,CDCl3)δ162.9(d,J C–F =243.5Hz),149.2,147.6,137.3(d,J C–F =2.6Hz), 129.7(d,J) C–F =7.7Hz),128.3,128.1127.3,127.1,126.0(d,J C–F =42.6Hz),115.0,114.8,78.6,71.1,65.0,62.8,60.2,41.6,23.9,22.5,20.8,10.9. 19 F NMR(376MHz,CDCl3)δ-116.8.HRMS(ESI)calculated for C 29 H 35 FNO[M+H] + :432.2703,found:432.2704.

[0160] In various embodiments, by using different catalysts, the yield of product 4b was 75-86%.

[0161] The NMR characterization results of product 4c are as follows: 1 H NMR (400MHz, CDCl3) δ7.29–7.02(m,5H),4.60(d,J=13.8Hz,1H),3.45–3.37(m,1H),3.34–3.30(m,1H),3.12(d,J=13.9Hz,1H), 2.78(t,J=8.7Hz,1H),2.67(d,J=9.7Hz,1H),1.88(d,J=9.7Hz,1H),1.58–1.51(m,1H),1.32–1.19(m,14H),1.06–1.01(m,6H). 13 C NMR(101MHz, CDCl3)δ141.9,128.1,128.1,126.2,78.5,69.1,60.5,56.1,39.4,38.4,38.0,26.2,23.6,23.4,20.4,16.2.HRMS(ESI)calculatedfor C 21 H 34 NO[M+H] + :316.2640,found:316.2643.

[0162] The yield of product 4c was 69%.

[0163] In other embodiments, the molar ratio of the benzyl compound, electrolyte, catalyst, and iodine source additive is 2:3.75:1:4, 4:3.75:3:2, or 3:3.75:2:3; the concentration of the benzyl compound in the organic solvent is not less than 0.0166 mol / L; the chemical reaction time is a certain time from 3 to 5 hours, such as 3 hours, 4 hours, 4.5 hours, or 5 hours; the reaction temperature is a certain temperature from -10 to 10°C, such as -10°C, -6°C, 3°C, or 10°C; and the organic solvent is a mixed solvent made of acetonitrile and ethanol in a volume ratio of 1:1, 7:1, or 10:1. All of these methods successfully yielded proline alcohol compounds.

[0164] It should be noted that the above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art can still modify the technical solutions described in the above embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A method for electrochemical synthesis of propanolamine compounds, characterized by, A prolinol compound is prepared by electrochemical reaction of a benzyl-containing compound, electrolyte, catalyst and iodine source additive in an organic solvent; The benzyl-containing compound has the following structural formula: ； The prolinol compound has the following structural formula: ； wherein R 1 is -Ph, cyclohexyl or -H; R 2 is -H; R 3 -H, -F, -Br, -CH3, -NO 2、 i-Pr or OMe; R 4 =OEt, OMe or n-Pr; The molar ratio of the benzyl-containing compound, electrolyte, catalyst and iodine source additive is 2-4:3.75:1-3:2-4. The concentration of the benzyl-containing compound in the organic solvent is not less than 0.0166 mol / L.

2. The electrochemical synthesis method of proline compounds according to claim 1, characterized in that, The electrochemical reaction is electrolysis at constant current. The electrochemical reaction is performed for 3-5 h at a reaction temperature of -10-10 °C.

3. The electrochemical synthesis method of proline compounds according to claim 2, characterized in that, The anode electrode used in electrolysis is a carbon electrode, and the cathode electrode is a platinum sheet electrode.

4. The electrochemical synthesis method of proline compounds according to claim 3, characterized in that, The electrolyte is tetrabutylammonium hexafluorophosphate.

5. The electrochemical synthesis method of proline compounds according to claim 4, characterized in that, The catalyst is a metal Salen complex.

6. The electrochemical synthesis method of proline compounds according to claim 5, characterized in that, The iodine source additive is iodobenzene.

7. The electrochemical synthesis method of proline compounds according to claim 6, characterized in that, The organic solvent is a mixed solvent prepared by mixing acetonitrile and ethanol at a volume ratio of 1-10:

1.

8. The electrochemical synthesis method of proline compounds according to any one of claims 1 to 7, characterized in that, After the electrochemical reaction is completed, the residue of the reaction liquid after removal of the organic solvent is separated and purified to obtain the prolinol compound.

9. The electrochemical synthesis method of proline compounds according to claim 8, characterized in that, The separation and purification is performed by silica gel column chromatography purification.

10. Use of an electrochemical synthesis method of prolinols according to any one of claims 1 to 9, characterized in that, The prolinol compound can be used for preparing an antitumor drug.

Images