Synthesis method of far-end amino alcohol compound

Abstract

The invention relates to a synthesis method of a far-end amino alcohol compound, which comprises the following steps: electrolyzing a cyclic amine compound shown as a formula (I) to obtain the far-end amino alcohol compound shown as a formula (II). According to the method, the cyclic amine and (high) proline peptide compounds are directly electrolyzed by adopting an electrochemical method, so that the far-end amino alcohol compounds can be obtained, a reaction precursor does not need to be prepared in advance, the use of a noble metal catalyst and a stoichiometric oxidant is avoided, the generation of chemical wastes is avoided, and the atom economy is favorably realized. The method has the advantages of simple operation, high product purity, easy purification, high efficiency and yield, low production cost, mild reaction conditions and no need of inert gas protection. And water is used as a green solvent and a hydroxyl source, so that the reaction system is more green, environment-friendly, safe, economical, energy-saving and environment-friendly, and industrial production is more favorably realized. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for synthesizing a remote amino alcohol compound. Background Art

[0002] Amino alcohols have amine (NHx) and hydroxyl (OH) functional groups, can bind to Lewis acids and transition metals, and are of great value in the fields of synthetic chemistry, materials science, and polymer chemistry. Amino alcohols can be used as surfactants, petroleum additives, organic synthesis raw materials, pharmaceutical intermediates, etc. Many drugs widely used in clinical practice contain amino alcohol structural units. In addition, it can also be used as a corrosion inhibitor for boiler water treatment or as a coolant for automobile engines. Most of the current research focuses on 1,2-amino alcohols, and there are relatively few studies on distal amino alcohols (such as 1,3-, 1,4-, 1,5-, 1,6-, and 1,7-amino alcohols). The construction of distal amino alcohols has been restricted due to the limitations of starting materials and methods. Traditional methods include azoaldehyde condensation (Chem. Commun. 2014, 50, 942.), metal-mediated olefin functionalization (J.Am.Chem.Soc.2021, 143, 12467. Angew.Chem.Int.Ed.2023, 62, e202305669.), intermolecular CH amination of alkanes (J.Am.Chem.Soc.2018, 140, 1612. Org.Lett.2021, 23, 8968.), and nucleophilic addition of semicyclic N, O-acetals (J.Am.Chem.Soc.2001, 123, 12510. J.Org.Chem.2019, 84, 11261.), etc. However, these methods usually require the preparation of reaction precursors in advance or can only be obtained by heating, noble metal photocatalysis or reaction-sensitive Grignard reagents. The reaction steps are complicated, the conditions are harsh, and the environment is harmful. In addition, they mainly produce 1,3- and 1,4-amino alcohols, and are rarely used for more distal 1,5-amino alcohols and other compounds. Therefore, it is urgent to develop a general method that can directly synthesize distal amino alcohols. Summary of the invention

[0003] Based on this, the object of the present invention is to provide a method for synthesizing a remote amino alcohol compound.

[0004] The technical solutions for achieving the above-mentioned purpose include the following.

[0005] A method for synthesizing a distal amino alcohol compound comprises the following steps:

[0006] Electrolyzing the cyclic amine compound represented by formula (I) to obtain the distal amino alcohol compound represented by formula (II),

[0007]

[0008] Among them, R 1 Selected from: aryl, arylformyl, alkylacyl;

[0009] Each R 2 are independently selected from: hydrogen, alkoxy, halogen, aryl, alkyl, alkoxycarbonyl, or two adjacent R 2 Together with the carbon atom to which it is attached, it forms a cycloalkyl group;

[0010] R is selected from: hydrogen, alkoxy, halogen, aryl, alkyl,

[0011] Each R 3 are independently selected from: a group after an amino hydrogen is removed from an amino acid or its ester, a group after an amino hydrogen is removed from a dipeptide or its ester, a group after an amino hydrogen is removed from a tripeptide or its ester, R 4 Substituted or unsubstituted alkylamino, R 4 Substituted or unsubstituted cycloalkylamino, R 4 Substituted or unsubstituted alkoxy, R 4 a substituted or unsubstituted cycloalkoxy group;

[0012] Each R 4 Each of the following is independently selected from the group consisting of: amino, protected amino, cyano, alkenyl, and alkoxycarbonyl;

[0013] R 5 Selected from: hydrogen, methyl, ethyl;

[0014] R 6 Selected from: hydrogen, methoxy, ethoxy;

[0015] n is selected from: 0, 1, 2, 3, 4;

[0016] m is selected from: 0, 1, 2, 3, 4, 5, 6.

[0017] In some embodiments, the cyclic amine compound has a structure shown in the following formula (III):

[0018]

[0019] The distal amino alcohol compound has a structure shown in the following formula (IV):

[0020]

[0021] n is selected from: 0, 1, 2, 3, 4;

[0022] m is selected from: 0, 1, 2, 3.

[0023] In some embodiments, the cyclic amine compound has a structure as shown in the following formula (V):

[0024]

[0025] The distal amino alcohol compound has a structure shown in the following formula (VI):

[0026]

[0027] n is selected from: 1, 2, 3.

[0028] In some embodiments, R 1 Selected from: C6-C 10 Aryl, C6-C 10 Arylformyl, C1-C 12 Alkyl acyl.

[0029] In some embodiments, R 1 Selected from: phenyl, benzoyl, C1-C6 alkyl acyl.

[0030] In some embodiments, R 1 Selected from: phenyl, benzoyl, pivaloyl.

[0031] In some embodiments, each R 2 are independently selected from: hydrogen, C1-C 12 Alkoxy, halogen, C6-C 10 Aryl, C1-C 12 Alkyl, C1-C 12 Alkoxycarbonyl, or two adjacent R2 together with the carbon atom to which they are attached form a C3-C 12 Cycloalkyl.

[0032] In some embodiments, each R 2 are independently selected from: hydrogen, C1-C6 alkoxy, halogen, C6-C 10 Aryl, C1-C6 alkyl, C1-C6 alkoxycarbonyl, or two adjacent R2 together with the carbon atom to which they are attached form a C3-C8 cycloalkyl.

[0033] In some embodiments, each R 2 are independently selected from: hydrogen, C1-C3 alkoxy, halogen, phenyl, C1-C3 alkyl, C1-C3 alkoxycarbonyl, or two adjacent R 2 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group.

[0034] In some embodiments, each R 2are independently selected from: hydrogen, methoxy, fluorine, phenyl, chlorine, methyl, methoxycarbonyl, or two adjacent R 2 Together with the carbon atom to which it is connected, it forms a cyclopropyl or cyclopentyl group.

[0035] In some embodiments, R is selected from: hydrogen, C1-C 12 Alkoxy, halogen, C6-C 10 Aryl, C1-C 12 alkyl,

[0036] Each R 3 are independently selected from: a group after an amino hydrogen is removed from an amino acid or its ester, a group after an amino hydrogen is removed from a dipeptide or its ester, a group after an amino hydrogen is removed from a tripeptide or its ester, R 4 Substituted or unsubstituted C1-C 12 Alkylamino, R 4 Substituted or unsubstituted C3-C 12 Cycloalkylamino, R 4 Substituted or unsubstituted C1-C 12 Alkoxy, R 4 Substituted or unsubstituted C3-C 12 Cycloalkoxy;

[0037] Each R 4 are independently selected from: amino, protected amino, cyano, alkenyl, C1-C 12 Alkoxycarbonyl.

[0038] In some embodiments, R is selected from the group consisting of hydrogen, C1-C6 alkoxy, halogen, C6-C 10 Aryl, C1-C6 alkyl,

[0039] Each R 3 are independently selected from: a group after an amino hydrogen is removed from an amino acid or its ester, a group after an amino hydrogen is removed from a dipeptide or its ester, a group after an amino hydrogen is removed from a tripeptide or its ester, R 4 Substituted or unsubstituted C1-C6 alkylamino, R 4 Substituted or unsubstituted C3-C 10 Cycloalkylamino, R 4 Substituted or unsubstituted C1-C6 alkoxy, R 4 Substituted or unsubstituted C3-C8 cycloalkoxy;

[0040] Each R 4 Each of the following is independently selected from the group consisting of amino, protected amino, cyano, alkenyl, and C1-C6 alkoxycarbonyl.

[0041] In some embodiments, R is selected from: hydrogen, methoxy, fluorine, phenyl, chlorine, methyl, methoxycarbonyl, or a group selected from the following structures:

[0042]

[0043] In some embodiments, the cyclic amine compound is selected from the following compounds:

[0044]

[0045]

[0046] The distal amino alcohol compound is selected from the following compounds:

[0047]

[0048]

[0049] In some of these embodiments, the electrolysis is performed in a single-chamber electrolysis cell containing an electrolyte.

[0050] In some embodiments, the solvent in the electrolyte is water, methanol, ethanol, acetone, or a mixed solvent of acetone and water.

[0051] In some embodiments, the volume ratio of acetone to water in the mixed solvent of acetone and water is 1:1-8.

[0052] In some of the embodiments, the volume ratio of acetone to water in the mixed solvent of acetone and water is 1:6-8.

[0053] In some embodiments, R 5 and R 6 The electrolyte is hydrogen, and the solvent in the electrolyte is water, or a mixed solvent of acetone and water.

[0054] In some embodiments, R 5 is methyl, R 6 is a methoxy group, and the solvent in the electrolyte is methanol.

[0055] In some embodiments, R 5 Ethyl, R 6 The solvent in the electrolyte is ethanol.

[0056] In some of the embodiments, the electrolyte in the electrolyte is one or more of tetrabutylammonium hydrogen sulfate, ammonium sulfate and tetrabutylammonium perchlorate.

[0057] In some embodiments, copper compounds are added to the electrolyte.

[0058] In some embodiments, the copper compound is one or more of tetraacetonitrile copper tetrafluoroborate, tetraacetonitrile copper hexafluorophosphate, copper trifluoromethanesulfonate, cupric chloride, cuprous chloride, cupric bromide and cuprous iodide.

[0059] In some embodiments, the molar ratio of the cyclic amine compound to the electrolyte is 1:0.5-1.5.

[0060] In some embodiments, the molar ratio of the cyclic amine compound to the electrolyte is 1:0.8-1.2.

[0061] In some of the embodiments, the molar concentration of the electrolyte in the electrolyte is 0.02 mmol / mL-0.08 mmol / mL.

[0062] In some of the embodiments, the molar concentration of the electrolyte in the electrolyte is 0.04 mmol / mL-0.06 mmol / mL.

[0063] In some embodiments, the molar ratio of the cyclic amine compound to the copper compound is 1:0.1-0.8.

[0064] In some embodiments, the molar ratio of the cyclic amine compound to the copper compound is 1:0.2-0.5.

[0065] In some embodiments, the molar ratio of the cyclic amine compound to the copper compound is 1:0.2-0.3.

[0066] In some embodiments, the molar ratio of the cyclic amine compound to the copper compound is 1:0.4-0.5.

[0067] In some of the embodiments, the molar concentration of the copper compound in the electrolyte is 0.004 mmol / mL-0.04 mmol / mL.

[0068] In some of the embodiments, the molar concentration of the copper compound in the electrolyte is 0.01 mmol / mL-0.025 mmol / mL.

[0069] In some embodiments, the anode for electrolysis is a graphite sheet or carbon felt, and the cathode is a graphite sheet, carbon felt, platinum sheet or copper sheet.

[0070] In some of the embodiments, the electrolysis is performed using a constant current with a current intensity of 4 mA to 30 mA, and the amount of current applied is 4.5 F / mol to 34 F / mol based on the amount of the cyclic amine compound.

[0071] In some embodiments, the current intensity is 8 mA to 20 mA, and the amount of current applied is 8.9 F / mol to 22.5 F / mol based on the amount of the cyclic amine compound.

[0072] In some embodiments, the current intensity is 6 mA to 10 mA, and the amount of current applied is 6.7 F / mol to 11.3 F / mol based on the amount of the cyclic amine compound.

[0073] In some embodiments, the current intensity is 12 mA to 20 mA, and the amount of current applied is 13.3 F / mol to 22.5 F / mol based on the amount of the cyclic amine compound.

[0074] In some embodiments, the electrolysis temperature is 20°C-30°C.

[0075] The present invention provides an innovative method for synthesizing distal amino alcohols, which can directly synthesize distal amino alcohol compounds through the electrochemical ring-opening reaction of cyclic amines. Compared with the prior art, the electrochemical synthesis method of distal amino alcohol compounds of the present invention has the following advantages:

[0076] Continuous paired electrolysis is carried out under mild, biocompatible reaction conditions, without the need for heating or inert gas protection, avoiding the use of precious metal catalysts and stoichiometric oxidants, greatly reducing the difficulty of purifying the reaction products. Electrons are used as oxidants during the reaction, and the reaction system is clean and environmentally friendly, avoiding the generation of chemical waste and helping to achieve atom economy.

[0077] The method is simple to operate and does not require the preparation of reaction precursors. It can directly prepare various remote amino alcohols and peptide alcohols in one step through the electrochemical ring opening of cyclic amines with water or alcohols. The products are high in purity, easy to purify, high in efficiency and yield, and low in production cost.

[0078] The method utilizes water or alcohol as a green solvent and a hydroxyl source or an alkoxy source, and the reaction system is greener, more environmentally friendly, safer, more economical, more energy-saving and more environmentally friendly, and is more conducive to industrial production. DETAILED DESCRIPTION

[0079] In order to facilitate the understanding of the present invention, the present invention will be described more fully below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0080] The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or conditions recommended by the manufacturers.

[0081] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used in the present invention includes any and all combinations of one or more of the related listed items.

[0082] In addition, as used in the present invention, the term "or" is an inclusive "or" symbol and is equivalent to the term "and / or", unless the context clearly dictates otherwise. The term "based on" is not exclusive and allows for being based on other factors not described, unless the context clearly dictates otherwise. In addition, throughout the specification, the meanings of "a", "an", and "the" include plural referents. The meaning of "in..." includes "in..." and "on...".

[0083] In the compounds described in the present invention, when any variable (such as R 2 If a (, etc.) compound occurs more than once in any component, its definition at each occurrence is independent of its definition at every other occurrence. Likewise, combinations of substituents and variables are permitted so long as such combinations render the compound stable. A line drawn from a substituent into a ring system or carbon chain indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, this means that such bonds are attached only to any suitable carbon atom of an adjacent ring. It is to be understood that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the invention to provide compounds that are chemically stable and that can be readily synthesized from readily available raw materials by techniques in the art and the methods set forth below. If a substituent is itself substituted with more than one group, it is to be understood that these groups may be on the same carbon atom or on different carbon atoms so long as the structure is stable.

[0084] The term "alkyl" as used herein is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms. For example, the definition of "C1-C6" in "C1-C6 alkyl" includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight or branched chain. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and hexyl.

[0085] The term "cycloalkyl" used in the present invention refers to a saturated or unsaturated non-aromatic monocyclic, condensed, bridged, or spirocyclic hydrocarbon group having a specific number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0086] The term "alkoxy" used in the present invention refers to a group having an -O-alkyl structure, such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -O-CH2CH(CH3)2, -OCH2CH2CH2CH3, -O-CH(CH3)2, etc.

[0087] The term "halogen" as used herein refers to chlorine, fluorine, bromine and iodine.

[0088] In the compounds of the present invention, Piv refers to pivaloyl, i.e., trimethylacetyl; and Bz refers to benzoyl.

[0089] The room temperature described in the present invention refers to 23°C-25°C.

[0090] The present invention is further described in detail below with reference to specific embodiments.

[0091] The starting materials and reagents used in the following examples are all commercially available conventional materials and reagents, or the substrates required for electrolysis can be synthesized by known methods reported in the literature.

[0092] Example 1: Electrochemical synthesis of compound 1b

[0093]

[0094] In a 30mL single-chamber electrolytic cell, raw material 1a (0.2mmol), Cu(MeCN)4BF4 (0.04mmol, i.e. 20% of raw material 1a) and electrolyte Bu4NHSO4 (0.2mmol) were added to 4mL of water, and electrolysis was carried out at a constant current of 8mA using a graphite sheet electrode as anode and a graphite sheet electrode as cathode. The electrolysis was stopped after stirring at room temperature for 6 hours, and the reaction solution was transferred, concentrated, and separated and purified by column chromatography to obtain 1b as a colorless liquid with a yield of 82%.

[0095] The characterization data of compound 1b are as follows: 1 H NMR (400MHz, CDCl3) δ = 5.78 (s, 1H), 3.61 (t, J = 6.4Hz, 2H), 3.22 (dd, J = 13.0, 6.8Hz, 2H), 1.61-1.46 (m, 4H), 1.42-1.34 (m, 2H), 1.16 (s, 9H);

[0096] 13 C NMR (100MHz, CDCl3) δ = 178.8, 62.5, 39.5, 38.7, 32.2, 29.5, 27.7, 23.1;

[0097] HR-MS(ESI)m / z calcd for:C 10 H22 NO2[M+H] + 188.1645, found 188.1638.

[0098] Example 2: Electrochemical synthesis of compound 2b

[0099]

[0100] Using 2a (0.2 mmol) as the starting material, according to the method and reaction conditions of Example 1, 2b was prepared as a colorless liquid with a yield of 59%.

[0101] The characterization data of compound 2b are as follows: 1 H NMR(400MHz, CDCl3)δ=7.78-7.72(m,2H),7.49-7.44(m,1H),7.43-7.36(m,2H),6.46(s,1H) ,3.63(t,J=6.3Hz,2H),3.44(dd,J=13.0,6.9Hz,2H),1.67-1.55(m,4H),1.49-1.39(m,4H);

[0102] 13 C NMR (100MHz, CDCl3) δ = 167.9, 134.8, 131.5, 128.6, 127.0, 62.6, 40.0, 32.2, 29.5, 23.2;

[0103] MS(ESI)m / z calcd for:C 12 H 18 NO2[M+H] + 208.1332, found 208.1334.

[0104] Example 3: Electrochemical synthesis of compound 3b

[0105]

[0106] Using 3a (0.2 mmol) as the starting material, according to the method and reaction conditions of Example 1, 3b was prepared as a colorless liquid with a yield of 59%.

[0107] The characterization data of compound 3b are as follows: 1 H NMR (400MHz, CDCl3) δ = 6.38 (s, 1H), 3.80-3.66 (m, 2H), 3.55-3.45 (m, 1H), 3.39-3.23 (m, 5H), 1.85-1.72 (m, 3H), 1.72-1.62 (m, 1H), 1.15 (s, 9H);

[0108] 13 C NMR (100MHz, CDCl3) δ = 178.8, 79.3, 60.0, 56.7, 38.7, 37.0, 35.4, 32.2, 27.6;

[0109] HR-MS(ESI)m / z calcd for:C 11 H 24 NO3[M+H] + 218.1751, found 218.1751.

[0110] Example 4: Electrochemical synthesis of compound 4b

[0111]

[0112] Using 4a (0.2 mmol) as the starting material, according to the method and reaction conditions of Example 1, 4b was prepared as a colorless liquid with a yield of 62%.

[0113] The characterization data of compound 4b are as follows: 1 H NMR (400MHz, CDCl3) δ = 6.15 (s, 1H), 3.83 (t, J = 6.1Hz, 2H), 3.45 (q, J = 6.3Hz, 2H), 2.20-2.07 (m, 4H), 1.16 (s, 9H);

[0114] 13 C NMR(100MHz, CDCl3)δ=179.1,124.9(t, 1 J C-F =240.7Hz Hz),56.7(t, 3 J C-F =6.1Hz),39.3(t, 2 J C-F =24.3Hz),38.7,36.2(t, 2 J C-F =24.2Hz),33.8(t, 3 J C-F =5.2Hz),27.5;

[0115] 19 F NMR (376MHz, CDCl3) δ = -95.39 (m).

[0116] HR-MS(ESI)m / z calcd for:C 10 H 20 F2NO2[M+H] +224.1457, found 224.1458.

[0117] Example 5: Electrochemical synthesis of compound 5b

[0118]

[0119] Using 5a (0.2 mmol) as raw material, according to the method and reaction conditions of Example 1, 5b was prepared as a brown liquid with a yield of 49%.

[0120] The characterization data of compound 5b are as follows: 1 H NMR(400MHz, CDCl3)δ=7.34v7.28(m,2H),7.24-7.16(m,3H),5.51(s,1H),3.59-3.39(m,2H) ),3.27-3.05(m,2H),2.83-2.71(m,1H),1.98-1.90(m,2H),1.86-1.75(m,2H),1.08(s,9H);

[0121] 13 C NMR (100MHz, CDCl3) δ = 178.7, 144.5, 128.9, 127.7, 126.8, 60.7, 40.5, 39.5, 38.7, 38.4, 36.5, 27.6;

[0122] HR-MS(ESI)m / z calcd for:C 16 H 26 NO2[M+H] + 264.1958, found 264.1958.

[0123] Example 6: Electrochemical synthesis of compound 6b

[0124]

[0125] Using 6a (0.2 mmol) as the starting material, according to the method and reaction conditions of Example 1, 6b was prepared as a colorless liquid with a yield of 39%.

[0126] The characterization data of compound 6b are as follows: 1 H NMR (400MHz, CDCl3) δ = 6.02 (s, 1H), 4.20-4.11 (m, 1H), 3.86-3.75 (m, 2H), 3.53-3.31 (m, 2H), 2.13-2.01 (m, 2H), 1.96-1.83 (m, 2H), 1.18 (s, 9H);

[0127] 13 C NMR (100MHz, CDCl3) δ = 179.2, 59.4, 58.3, 40.9, 38.8, 38.1, 37.3, 27.7;

[0128] HR-MS(ESI)m / z calcd for:C 10 H 21 ClNO2[M+H] + 222.1255, found 222.1257.

[0129] Example 7: Electrochemical synthesis of compound 7b

[0130]

[0131] Using 7a (0.2 mmol) as the starting material, according to the method and reaction conditions of Example 1, 7b was prepared as a colorless liquid with a yield of 74%.

[0132] The characterization data of compound 7b are as follows: 1 H NMR (400MHz, CDCl3) δ = 5.41 (d, J = 7.2Hz, 1H), 4.02-3.89 (m, 1H), 3.66-3.54 (m, 2H),1.63-1.48(m,2H),1.47-1.30(m,4H),1.16(s,9H),1.10(d,J=6.6Hz,3H);

[0133] 13 C NMR (100MHz, CDCl3) δ = 178.1, 62.6, 44.9, 38.7, 36.9, 32.4, 27.7, 22.3, 21.1;

[0134] HR-MS(ESI)m / z calcd for:C 11 H 24 NO2[M+H] + 202.1802, found 202.1801.

[0135] Example 8: Electrochemical synthesis of compound 8b

[0136]

[0137] Using 8a (0.2 mmol) as the starting material, according to the method and reaction conditions of Example 1, 8b was prepared as a colorless liquid with a yield of 67%.

[0138] The characterization data of compound 8b are as follows: 1H NMR (400MHz, CDCl3) δ = 5.78 (s, 1H), 3.66-3.41 (m, 2H), 3.29-3.01 (m, 2H), 1.72-1.26 (m, 5H), 1.18 (s, 9H), 0.90 (d, J = 1.8Hz, 3H);

[0139] 13 C NMR (100MHz, CDCl3) δ=178.9,178.8,68.0,62.9,45.1,39.7,38.9,38.8,35.3,33.3,30.3,30.2,29.8,27.74,27.71,27.1,17.8,16.7;

[0140] HR-MS(ESI)m / z calcd for:C 11 H 24 NO2[M+H] + 202.1802, found 202.1803.

[0141] Example 9: Electrochemical synthesis of compound 9b

[0142]

[0143] Using 9a (0.2 mmol) as the starting material, according to the method and reaction conditions of Example 1, 9b was prepared as a colorless liquid with a yield of 51%.

[0144] The characterization data of compound 9b are as follows: 1 H NMR (400MHz, CDCl3) δ = 6.20 (d, J = 7.8Hz, 1H), 4.64-4.55 (m, 1H), 3.74 (s, 3H), 3.67- 3.58(m,2H),1.91-1.82(m,1H),1.73-1.51(m,3H),1.47-1.32(m,2H),1.21(s,9H);

[0145] 13 C NMR (100MHz, CDCl3) δ = 178.6, 173.5, 62.5, 52.5, 51.9, 38.9, 32.5, 32.1, 27.6, 21.6;

[0146] HR-MS(ESI)m / z calcd for:C 12 H 24 NO4[M+H] + 246.1700, found 246.1700.

[0147] Example 10: Electrochemical synthesis of compound 10b

[0148]

[0149] Using 10a as the raw material, according to the method and reaction conditions of Example 1, 10b was prepared as a colorless liquid with a yield of 68%.

[0150] The characterization data of compound 10b are as follows: 1 H NMR (400MHz, CDCl3) δ = 6.00 (s, 1H), 3.65 (t, J = 5.8Hz, 2H), 3.25 (q, J = 6.5Hz, 2H), 1.62-1.53 ​​(m, 4H), 1.17 (s, 9H);

[0151] 13 C NMR (100MHz, CDCl3) δ = 179.0, 62.3, 39.4, 38.8, 29.7, 27.7, 26.3;

[0152] HR-MS(ESI)m / z calcd for:C9H 20 NO2[M+H] + 174.1489, found 174.1491.

[0153] Example 11: Electrochemical synthesis of compound 11b

[0154]

[0155] Using 11a (0.2 mmol) as the starting material, according to the method and reaction conditions of Example 1, 11b was prepared as a colorless liquid with a yield of 50%.

[0156] The characterization data of compound 11b are as follows: 1 HNMR (400MHz, CDCl3) δ = 6.48 (d, J = 7.1Hz, 1H), 4.62-4.54 (m, 1H), 3.73 (s, 3H), 3.65 (t ,J=5.7Hz,2H),1.98-1.87(m,1H),1.84-1.72(m,1H),1.62-1.53(m,2H),1.19(s,9H);

[0157] 13 C NMR (100MHz, CDCl3) δ = 178.8, 173.4, 62.0, 52.5, 51.9, 38.8, 29.4, 28.2, 27.5;

[0158] HR-MS(ESI)m / z calcd for:C11 H 22 NO4[M+H] + 232.1543, found 232.1545.

[0159] Example 12: Electrochemical synthesis of compound 12b

[0160]

[0161] Using 12a as the starting material, according to the method and reaction conditions of Example 1, 12b was prepared as a brown solid with a yield of 78%.

[0162] The characterization data of compound 12b are as follows: 1 H NMR(400MHz, CDCl3)δ=7.79-7.71(m,2H),7.49-7.42(m,1H),7.42-7.34(m,2H) ,6.84(s,1H),3.67(t,J=5.9Hz,2H),3.45(q,J=6.5Hz,2H),1.76-1.56(m,4H);

[0163] 13 C NMR (100MHz, CDCl3) δ = 168.0, 134.7, 131.5, 128.6, 127.0, 62.3, 39.9, 29.9, 26.3;

[0164] HR-MS(ESI)m / z calcd for:C 11 H 16 NO2[M+H] + 194.1176, found 194.1179.

[0165] Example 13: Electrochemical synthesis of compound 13b

[0166]

[0167] Using 13a (0.2 mmol) as starting material, according to the method and reaction conditions of Example 1, 13b was prepared as a white solid in a yield of 56%.

[0168] The characterization data of compound 13b are as follows: 1H NMR (400MHz, CDCl3) δ = 6.73 (s, 1H), 4.07 (dd, J = 11.8, 4.8Hz, 1H), 3.87-3.78 (m, 1H), 3.56 (s, 1H), 3.23 (t, J =11.3Hz,1H),2.83-2.72(m,1H),1.17(s,9H),1.07-0.97(m,1H),0.76-0.66(m,1H),0.06(q,J=5.4Hz,1H);

[0169] 13 C NMR (100MHz, CDCl3) δ = 179.1, 62.4, 38.9, 38.8, 27.6, 18.0, 15.8, 7.4;

[0170] HR-MS(ESI)m / z calcd for:C 10 H 19 NO2Na + [M+Na] + 208.1308, found 208.1306.

[0171] Example 14: Electrochemical synthesis of compound 14b

[0172]

[0173] Using 14a as the starting material, according to the method and reaction conditions of Example 1, 14b was prepared as a colorless liquid with a yield of 38%.

[0174] The characterization data of compound 14b are as follows: 1 H NMR (400MHz, CDCl3) δ = 6.15 (s, 1H), 3.59 (t, J = 5.5Hz, 2H), 3.41 (dd, J = 12.1, 6.1Hz, 2H), 1.71-1.62 (m, 2H), 1.20 (s, 9H);

[0175] 13 C NMR (100MHz, CDCl3) δ = 180.2, 59.3, 38.8, 36.3, 32.4, 27.7;

[0176] HR-MS(ESI)m / z calcd for:C8H 18 NO2[M+H] + 160.1332, found 160.1324.

[0177] Example 15: Electrochemical synthesis of compound 15b

[0178]

[0179] Using 15a (0.2 mmol) as the starting material, according to the method and reaction conditions of Example 1, 15b was prepared as a colorless liquid with a yield of 52%.

[0180] The characterization data of compound 15b are as follows: 1 H NMR (400MHz, CDCl3) δ = 5.68 (s, 1H), 3.61 (t, J = 6.5Hz, 2H), 3.23 (dd, J = 13.1, 6.8Hz, 2H), 1.60-1.45 (m, 4H), 1.43-1.28 (m, 4H), 1.17 (s, 9H);

[0181] 13 C NMR (100MHz, CDCl3) δ = 178.7, 62.7, 39.4, 38.8, 32.6, 29.7, 27.7, 26.5, 25.3;

[0182] HR-MS(ESI)m / z calcd for:C 11 H 24 NO2[M+H] + 202.1802, found 202.1803.

[0183] Example 16: Electrochemical synthesis of compound 16b

[0184]

[0185] Using 16a (0.2 mmol) as the starting material, according to the method and reaction conditions of Example 1, 16b was prepared as a colorless liquid with a yield of 56%.

[0186] The characterization data of compound 16b are as follows: 1 H NMR (400MHz, CDCl3) δ = 5.68 (s, 1H), 3.60 (t, J = 6.6Hz, 2H), 3.20 (dd, J = 13.1, 7.0Hz, 2H), 1.58-1.42 (m, 4H), 1.36-1.27 (m, 6H), 1.16 (s, 9H);

[0187] 13 C NMR (100MHz, CDCl3) δ = 178.6, 62.8, 39.6, 38.7, 32.7, 29.6, 29.1, 27.7, 26.9, 25.7;

[0188] HR-MS(ESI)m / z calcd for:C 12H 26 NO2[M+H] + 216.1958, found 216.1960.

[0189] Example 17: Electrochemical synthesis of compound 17b

[0190]

[0191] Using 17a (0.2 mmol) as starting material, according to the method and reaction conditions of Example 1, 17b was prepared as a white solid in a yield of 58%.

[0192] The characterization data of compound 17b are as follows: 1 H NMR (400MHz, CDCl3) δ = 6.94 (s, 1H), 3.65-3.55 (m, 2H), 3.47-3.37 (m, 1H), 3.10-3.01 (m, 1H), 2.24-2 .09(m,2H),1.80-1.67(m,2H),1.66-1.57(m,1H),1.56-1.43(m,1H),1.34-1.21(m,2H),1.16(s,9H);

[0193] 13 C NMR (100MHz, CDCl3) δ = 178.7, 63.4, 43.6, 41.5, 40.3, 38.7, 29.8, 28.1, 27.7, 23.1;

[0194] HR-MS(ESI)m / z calcd for:C 12 H 23 NO2Na + [M+Na] + 236.1621, found 236.1614.

[0195] Example 18: Electrochemical synthesis of compound 18b

[0196]

[0197] In a 30 mL single-chamber electrolytic cell, raw material 1a (0.2 mmol), Cu(MeCN)4BF4 (0.04 mmol) and electrolyte Bu4NHSO4 (0.2 mmol) were added to 4 mL of methanol. A graphite sheet electrode was used as the anode and a graphite sheet electrode as the cathode. Electrolysis was performed at a constant current of 8 mA. After stirring at room temperature for 6 hours, the electrolysis was stopped. The reaction solution was transferred, concentrated, and purified by column chromatography to obtain 18b as a colorless liquid with a yield of 84%.

[0198] The characterization data of compound 18b are as follows: 1 H NMR (400MHz, CDCl3) δ = 5.73 (s, 1H), 4.31 (t, J = 5.7Hz, 1H), 3.27 (s, 6H), 3.19 (dd, J = 13 .0,6.9Hz,2H),1.61-1.53(m,2H),1.53-1.43(m,2H),1.38-1.29(m,2H),1.14(s,9H);

[0199] 13 C NMR (100MHz, CDCl3) δ = 178.5, 104.4, 52.8, 39.5, 38.7, 32.1, 29.4, 27.6, 21.9;

[0200] HR-MS(ESI)m / z calcd for:C 12 H 25 NO3Na + [M+Na] + 254.1727, found 254.1725.

[0201] Example 19: Electrochemical synthesis of compound 19b

[0202]

[0203] In a 30 mL single-chamber electrolytic cell, raw material 1a (0.2 mmol), Cu(MeCN)4BF4 (0.04 mmol) and electrolyte Bu4NHSO4 (0.2 mmol) were added to 4 mL of ethanol. A graphite sheet electrode was used as the anode and a graphite sheet electrode as the cathode. Electrolysis was performed at a constant current of 8 mA. After stirring at room temperature for 6 hours, the electrolysis was stopped. The reaction solution was transferred, concentrated, and purified by column chromatography to obtain 19b as a colorless liquid with a yield of 70%.

[0204] The characterization data of compound 19b are as follows: 1 H NMR (400MHz, CDCl3) δ = 5.69 (s, 1H), 4.43 (t, J = 5.7Hz, 1H), 3.65-3.54 (m, 2H), 3.50-3.39 (m, 2H), 3.20 (dd,J=12.8,7.0Hz,2H),1.63-1.55(m,2H),1.54-1.44(m,2H),1.39-1.31(m,2H),1.18-1.13(m,15H);

[0205] 13C NMR (100MHz, CDCl3) δ = 178.5, 102.8, 61.2, 39.5, 38.7, 33.3, 29.5, 27.7, 22.1, 15.4;

[0206] HR-MS(ESI)m / z calcd for:C 14 H 29 NO3Na + [M+Na] + 282.2040, found 282.2036.

[0207] Example 20: Electrochemical synthesis of compound 22b

[0208]

[0209] In a 30 mL single-chamber electrolytic cell, the raw material 22a (0.2 mmol), Cu(MeCN)4BF4 (0.1 mmol) and the electrolyte Bu4NHSO4 (0.2 mmol) were added to a mixed solvent of 4 mL acetone and water (volume ratio of 1:7), and electrolysis was carried out under the condition of 12 mA constant current with a graphite sheet electrode as anode and a graphite sheet electrode as cathode. The electrolysis was stopped after stirring at room temperature for 6 hours, and the reaction solution was transferred, concentrated, and separated and purified by column chromatography to obtain 22b as a colorless liquid with a yield of 52%.

[0210] The characterization data of compound 22b are as follows: 1 H NMR (400MHz, CDCl3) δ = 7.16 (d, J = 10.4Hz, 1H), 6.45 (d, J = 7.5Hz, 1H), 4.59-4.51 (m, 1H), 4.46 (dd, J = 8.6, 4.9Hz, 1H), 3.69 (s, 3H), 3.60 (t, J = 5.6H) z,2H),2.20-2.09(m,1H),1.97-1.84(m,1H),1.72-1.63(m,1H),1.65-1. 50(m,2H),1.47-1.36(m,2H),1.19(s,9H),0.90(dd,J=14.6,6.8Hz,6H);

[0211] 13 C NMR (100MHz, CDCl3) δ=179.0,172.3,62.3,57.4,52.7,52.3,38.9,32.3,32.1,31.1,27.5,21.9,19.2,17.8;

[0212] HR-MS(ESI)m / z calcd for:C 17 H32 N2O5Na + [M+Na] + 367.2204, found 367.2200.

[0213] Example 21: Electrochemical synthesis of compound 23b

[0214]

[0215] Using 23a (0.2 mmol) as starting material, according to the method and reaction conditions of Example 20, 23b was prepared as a white solid in a yield of 59%.

[0216] The characterization data of compound 23b are as follows: 1 HNMR (400MHz, CDCl3) δ = 7.26 (d, J = 8.2Hz, 1H), 6.49 (d, J = 7.9Hz, 1H), 4.57-4.49 (m, 2H), 3.68 (s, 3H), 3.60 (t, J =6.2Hz,2H),1.93-1.81(m,1H),1.71-1.49(m,6H),1.44-1.36(m,2H),1.18(s,9H),0.91(dd,J=6.1,4.7Hz,6H);

[0217] 13 C NMR (100MHz, CDCl3) δ=179.0,173.3,172.1,62.2,52.6,52.4,50.8,41.2,38.9,32.3,32.1,27.5,25.0,22.9,21.7;

[0218] HR-MS(ESI)m / z calcd for:C 18 H 34 N2O5Na + [M+Na] + 381.2360, found 381.2358.

[0219] Example 22: Electrochemical synthesis of compound 24b

[0220]

[0221] Using 24a (0.2 mmol) as starting material, according to the method and reaction conditions of Example 20, 24b was prepared as a colorless liquid with a yield of 69%.

[0222] The characterization data of compound 24b are as follows: 1HNMR (400MHz, CDCl3) δ = 7.07 (d, J = 8.7Hz, 1H), 6.39 (d, J = 8.0Hz, 1H), 4.56-4.47 (m, 2H), 3.70 (s, 3H), 3.62 (t, J = 6.2Hz, 2H), 1 .97-1.81(m,2H),1.74-1.52(m,3H),1.48-1.32(m,3H),1.30-1.19(m,1H),1.20(s,9H),1.18-1.11(m,1H),0.94-0.85(m,6H);

[0223] 13 C NMR (100MHz, CDCl3) δ=179.1,172.3,172.1,62.3,56.6,52.7,52.2,38.9,37.7,32.1,32.1,27.6,25.2,21.9,15.7,11.6;

[0224] HR-MS(ESI)m / z calcd for C 18 H 34 N2O5Na + [M+Na] + 381.2360, found 381.2354.

[0225] Example 23: Electrochemical synthesis of compound 25b

[0226]

[0227] Using 25a as the starting material, according to the method and reaction conditions of Example 20, 25b was prepared as a colorless liquid with a yield of 54%.

[0228] The characterization data of compound 25b are as follows: 1 HNMR (400MHz, CDCl3) δ = 6.77 (d, J = 9.1Hz, 1H), 6.40 (d, J = 7.7Hz, 1H), 4.60-4.51 (m, 1H), 4.43 (d, J = 9.2Hz, 1H), 4.22 (q, J = 6.2Hz, 1H), 3.69 (s, 3H), 3.64(t,J=6.3Hz,2H),1.97-1.88(m,1H),1.77-1.66(m,1H),1.66-1.55(m ,2H),1.50-1.39(m,2H),1.22(s,9H),1.15(d,J=6.2Hz,3H),1.09(s,9H);

[0229] 13C NMR (100MHz, CDCl3) δ=178.7,172.6,171.3,74.3,67.4,62.4,57.9,52.9,52.4,38.9,32.2,32.0,28.4,27.6,21.8,21.2;

[0230] HR-MS(ESI)m / z calcd for:C 20 H 39 N2O6[M+H] + 403.2803, found 403.2804.

[0231] Example 24: Electrochemical synthesis of compound 26b

[0232]

[0233] Using 26a (0.2 mmol) as starting material, according to the method and reaction conditions of Example 20, 26b was prepared as a colorless liquid with a yield of 48%.

[0234] The characterization data of compound 26b are as follows: 1 HNMR (400MHz, CDCl3) δ = 7.05 (d, J = 8.5Hz, 1H), 6.49 (d, J = 7.9Hz, 1H), 4.64 (dt, J = 8.3, 3.2Hz, 1H), 4.57-4.48 (m, 1H), 3.77 (dd, J = 9.1, 3.2Hz, 1H), 3 .70(s,3H),3.59(t,J=6.3Hz,2H),3.53(dd,J=9.1,3.2Hz,1H),1.94-1.8 1(m,1H),1.73-1.47(m,3H),1.45-1.34(m,2H),1.19(s,9H),1.10(s,9H);

[0235] 13 C NMR (100MHz, CDCl3) δ=178.8,172.0,170.9,73.6,62.2,61.8,53.0,52.6,52.5,38.9,32.1,32.0,27.6,27.3,21.7;

[0236] HR-MS(ESI)m / z calcd for C 19 H 36 N2O6Na + [M+Na] + 411.2466, found 411.2456.

[0237] Example 25: Electrochemical synthesis of compound 27b

[0238]

[0239] Using raw material 27a (0.2 mmol) as raw material, according to the method and reaction conditions of Example 20, 27b was prepared as a colorless liquid with a yield of 51%.

[0240] The characterization data of compound 27b are as follows: 1 H NMR (400MHz, CDCl3) δ = 7.34-7.19 (m, 3H), 7.19-7.09 (m, 3H), 6.41 (d, J = 7.9Hz, 1H), 4.89-4.79 (m, 1H), 4.53-4.43 (m, 1H), 3.71 (s, 3H), 3.56 (t, J=6.2Hz,2H),3.19(dd,J=14.0,5.3Hz,1H),3.01(dd,J=14.0,8.0Hz,1H),1.79-1.66(m,1H),1.58-1.42(m,3H),1.31-1.19(m,2H),1.18(s,9H);

[0241] 13 C NMR (100MHz, CDCl3) δ=178.9,172.0,171.9,136.1,129.3,128.7,127.2,62.3,53.3,52.5,38.9,38.0,32.3,32.1,27.5,21.5;

[0242] HR-MS(ESI)m / z calcd for C 21 H 32 N2O5Na + [M+Na] + 415.2204, found 415.2194.

[0243] Example 26: Electrochemical synthesis of compound 28b

[0244]

[0245] Using 28a (0.2 mmol) as starting material, according to the method and reaction conditions of Example 20, 28b was prepared as a colorless liquid with a yield of 57%.

[0246] The characterization data of compound 28b are as follows: 1HNMR (400MHz, CDCl3) δ = 7.34 (d, J = 7.1Hz, 1H), 6.40 (d, J = 7.9Hz, 1H), 4.60-4.46 (m, 2H), 3.71 (s, 3H), 3.66 (s, 3H), 3.62 (t, J=6.2Hz,2H),2.44-2.33(m,2H),2.26-2.14(m,1H),2.06-1.82(m,2H),1.74-1.51(m,3H),1.47-1.36(m,2H),1.19(s,9H);

[0247] 13 C NMR (100MHz, CDCl3) δ=179.0,173.3,172.2,172.1,62.2,52.7,52.1,51.7,38.9,32.2,32.0,30.1,27.5,27.1,21.8;

[0248] HR-MS(ESI)m / z calcd for:C 18 H 33 N2O7[M+H] + 389.2282, found 389.2285.

[0249] Example 27: Electrochemical synthesis of compound 29b

[0250]

[0251] Using 29a (0.2 mmol) as starting material, according to the method and reaction conditions of Example 20, 29b was prepared as a colorless liquid with a yield of 33%.

[0252] The characterization data of compound 29b are as follows: 1 HNMR (400MHz, CDCl3) δ = 7.18 (d, J = 7.9Hz, 1H), 6.46 (d, J = 7.7Hz, 1H), 4.85 (t, J = 6.0Hz, 1H), 4.59-4.45 (m, 2H), 3.70 (s, 3H), 3.6 2(t,J=5.6Hz,2H),3.13-3.01(m,2H),1.95-1.77(m,2H),1.75-1.63(m,2H),1.61-1.54(m,2H),1.50-1.33(m,15H),1.19(s,9H);

[0253] 13C NMR (100MHz, CDCl3) δ=178.9,172.6,172.0,156.3,79.3,62.2,52.8,52.5,52.1,40.3,38.9,32.3,32.0,31.8,29.6,28.5,27.6,22.7,21.8;

[0254] HR-MS(ESI)m / z calcd for C 23 H 43 N3O7Na + [M+Na] + 496.2994, found 496.2987.

[0255] Example 28: Electrochemical synthesis of compound 30b

[0256]

[0257] Using 30a (0.2 mmol) as starting material, according to the method and reaction conditions of Example 20, 30b was prepared as a colorless liquid with a yield of 77%.

[0258] The characterization data of compound 30b are as follows: 1 HNMR (400MHz, CDCl3) δ = 7.12 (d, J = 8.0Hz, 1H), 6.43 (d, J = 7.8Hz, 1H), 5.73-5.59 (m, 1H), 5.16-5.06 (m, 2H), 4.65-4.55 (m, 1H), 4.55-4. 46(m,1H),3.70(s,3H),3.60(t,J=6.3Hz,2H),2.63-2.40(m,3H),1.94-1.79(m,1H),1.71-1.49(m,3H),1.45-1.34(m,2H),1.19(s,9H);

[0259] 13 C NMR (100MHz, CDCl3) δ=179.0,172.0,171.9,132.3,119.3,62.3,52.6,52.5,51.8,38.9,36.4,32.3,32.1,27.5,21.8;

[0260] HR-MS(ESI)m / z calcd for:C 17 H 31 N2O5[M+H] + 343.2227, found 343.2230.

[0261] Example 29: Electrochemical synthesis of compound 31b

[0262]

[0263] Using 31a (0.2 mmol) as starting material, according to the method and reaction conditions of Example 20, 31b was prepared as a white solid in a yield of 59%.

[0264] The characterization data of compound 31b are as follows: 1 HNMR (400MHz, CDCl3) δ = 7.48 (d, J = 8.6Hz, 1H), 6.53 (d, J = 7.8Hz, 1H), 4.53-4.43 (m, 1H), 3.68 (s, 3H), 3.60 (t, J = 6.2 Hz,2H),2.31-2.09(m,2H),2.00-1.88(m,2H),1.87-1.69(m,5H),1.67-1.50(m,3H),1.46-1.35(m,2H),1.17(s,9H);

[0265] 13 C NMR (100MHz, CDCl3) δ = 178.9, 174.6, 171.8, 66.0, 62.2, 52.6, 52.4, 38.8, 37.4, 37.1, 32.2, 32.1, 27.5, 24.6, 24.6, 21.4;

[0266] HR-MS(ESI)m / z calcd for C 18 H 32 N2O5Na + [M+Na] + 379.2203, found 379.2200.

[0267] Example 30: Electrochemical synthesis of compound 32b

[0268]

[0269] In a 30 mL single-chamber electrolytic cell, the raw material 32a (0.2 mmol), Cu(MeCN)4BF4 (0.1 mmol) and the electrolyte Bu4NHSO4 (0.2 mmol) were added to a mixed solvent of 4 mL acetone and water (volume ratio of 1:7), and electrolysis was carried out at a constant current of 20 mA using a graphite sheet electrode as the anode and a graphite sheet electrode as the cathode. The electrolysis was stopped after stirring at room temperature for 4 hours, and the reaction solution was transferred, concentrated, and separated and purified by column chromatography to obtain 32b as a white solid in a yield of 50%.

[0270] The characterization data of compound 32b are as follows:1 HNMR (400MHz, CDCl3) δ = 7.19 (d, J = 7.8Hz, 1H), 6.61 (d, J = 7.5Hz, 1H), 4.67-4.59 (m, 1H), 4.56-4.47 (m, 1H), 3. 78-3.66(m,5H),1.99-1.90(m,1H),1.85-1.77(m,1H),1.75-1.53(m,5H),1.20(s,9H),0.91(t,J=6.1Hz,6H);

[0271] 13 C NMR (100MHz, CDCl3) δ=178.9,173.5,172.1,62.8,52.5,52.3,51.1,41.0,38.9,30.5,27.64,27.56,24.9,22.9,21.8;

[0272] HR-MS(ESI)m / z calcd for C 17 H 32 N2O5Na + [M+Na] + 367.2203, found 367.2196.

[0273] Example 31: Electrochemical synthesis of compound 33b

[0274]

[0275] Using 33a (0.2 mmol) as starting material, according to the method and reaction conditions of Example 30, 33b was prepared as a colorless liquid with a yield of 51%.

[0276] The characterization data of compound 33b are as follows: 1 HNMR (400MHz, CDCl3) δ = 7.45 (d, J = 7.5Hz, 1H), 6.67 (d, J = 7.6Hz, 1H), 4.69-4.60 (m, 1H), 4.56-4.46 ( m,1H),3.76-3.69(m,5H),1.98-1.77(m,2H),1.74-1.57(m,2H),1.40(d,J=7.3Hz,3H),1.19(s,9H);

[0277] 13 C NMR (100MHz, CDCl3) δ = 179.0, 173.5, 171.9, 62.6, 52.6, 52.3, 48.2, 38.9, 30.7, 27.61, 27.56, 17.8;

[0278] HR-MS(ESI)m / z calcd for:C 14 H 27 N2O5[M+H] + 303.1914, found 303.1916.

[0279] Example 32: Electrochemical synthesis of compound 34b

[0280]

[0281] Using 34a (0.2 mmol) as starting material, according to the method and reaction conditions of Example 30, 34b was prepared as a colorless liquid in a yield of 59%.

[0282] The characterization data of compound 34b are as follows: 1 HNMR (400MHz, CDCl3) δ = 6.96 (d, J = 9.1Hz, 1H), 6.65 (d, J = 7.7Hz, 1H), 4.71-4.62 (m, 1H), 4.45 (dd, J = 9.0, 1.8Hz, 1H), 4.50-4.40 (m ,1H),3.77-3.67(m,5H),2.02-1.93(m,1H),1.89-1.78(m,1H),1.74-1.60(m,2H),1.20(s,9H),1.16(d,J=6.2Hz,3H),1.10(s,9H);

[0283] 13 C NMR (100MHz, CDCl3) δ = 178.6, 172.6, 171.3, 74.4, 67.4, 62.6, 58.1, 52.6, 52.4, 38.9, 30.5, 28.4, 27.9, 27.6, 21.2;

[0284] HR-MS(ESI)m / z calcd for C 19 H 36 N2O6Na + [M+Na] + 411.2466, found 411.2463.

[0285] Example 33: Electrochemical synthesis of compound 35b

[0286]

[0287] Using 35a (0.2 mmol) as starting material, according to the method and reaction conditions of Example 30, 35b was prepared as a white solid in a yield of 64%.

[0288] The characterization data of compound 35b are as follows: 1 H NMR (400MHz, CDCl3) δ = 7.57 (s, 1H), 6.72 (d, J = 7.7Hz, 1H), 4.63-4.52 (m, 1H), 3.74-3.65 (m, 5 H),2.33-2.08(m,2H),1.99-1.85(m,3H),1.85-1.67(m,5H),1.69-1.54(m,2H),1.18(s,9H);

[0289] 13 C NMR (100MHz, CDCl3) δ=179.0,174.6,171.7,66.0,62.5,52.6,52.1,38.9,37.5,37.1,30.3,27.6,27.5,24.61,24.57;

[0290] HR-MS(ESI)m / z calcd for:C 17 H 31 N2O5[M+H] + 343.2227, found 343.2229.

[0291] Example 34: Electrochemical synthesis of compound 36b

[0292]

[0293] Using 36a (0.2 mmol) as starting material, according to the method and reaction conditions of Example 20, 36b was prepared as a colorless liquid with a yield of 60%.

[0294] The characterization data of compound 36b are as follows: 1 HNMR (400MHz, CDCl3) δ = 7.55 (t, J = 7.6Hz, 1H), 7.44 (d, J = 5.6Hz, 1H), 6.59 (d, J =6.2Hz,1H),4.58-4.47(m,1H),4.41-4.32(m,1H),4.04(dd,J=17.9,5.7Hz,1H) ,3.88(dd,J=17.9,5.3Hz,1H),3.70(s,3H),3.60(t,J=6.1Hz,2H),1.89-1.78(m ,1H),1.73-1.52(m,3H),1.48-1.40(m,2H),1.37(d,J=7.1Hz,3H),1.17(s,9H);

[0295] 13C NMR (100MHz, CDCl3) δ = 179.6, 172.8, 172.5, 170.5, 62.1, 53.6, 52.4, 49.0, 41.2, 38.8, 32.0, 31.9, 27.5, 22.0, 17.8;

[0296] HR-MS(ESI)m / z calcd for C 17 H 31 N3O6Na + [M+Na] + 396.2106, found 396.2100.

[0297] Example 35: Electrochemical synthesis of compound 37b

[0298]

[0299] Using 37a (0.2 mmol) as starting material, according to the method and reaction conditions of Example 20, 37b was prepared as a colorless liquid in a yield of 54%.

[0300] The characterization data of compound 37b are as follows: 1 H NMR (400MHz, CDCl3) δ=7.32-7.17(m,4H),7.16-7.08(m,2H),6.94(d,J=7.8Hz,1H),6.51(d,J=7.4Hz,1H),4.82-4.73(m,1H),4.50-4.38(m,2H),3 .69(s,3H),3.61(t,J=5.7Hz,2H),3.18-3.02(m,2H),1.91-1.79(m,1H), 1.74-1.49(m,3H),1.46-1.37(m,2H),1.31(d,J=7.1Hz,3H),1.20(s,9H);

[0301] 13 C NMR(100MHz, CDCl3)δ=179.2,172.1,171.9,171.9,136.1,129.4,128.6,12 7.2,62.2,53.6,53.1,52.5,49.1,38.8,37.8,32.3,32.0,27.5,21.9,18.1;

[0302] HR-MS(ESI)m / z calcd for C 24 H 37 N3O6Na + [M+Na] +486.2575, found 486.2567.

[0303] Example 36: Electrochemical synthesis of compound 38b

[0304]

[0305] Using 38a (0.2 mmol) as starting material, according to the method and reaction conditions of Example 20, 38b was prepared as a colorless liquid in a yield of 52%.

[0306] The characterization data of compound 38b are as follows: 1 HNMR(400MHz, CDCl3)δ=7.42(d,J=7.5Hz,1H),7.27(d,J=9.0Hz,1H),6.61(d,J=7.2H z,1H),4.55-4.47(m,1H),4.46-4.37(m,2H),3.69(s,3H),3.64(s,3H),3.59(t,J=7. 2Hz,2H),2.37(t,J=8.0Hz,2H),2.24-2.12(m,1H),2.06-1.94(m,1H),1.90-1.78(m, 1H),1.74-1.50(m,6H),1.46-1.35(m,2H),1.17(s,9H),0.89(dd,J=14.2,5.6Hz,6H);

[0307] 13 C NMR (100MHz, CDCl3) δ = 179.3, 173.4, 172.7, 172.3, 172.1, 62.1, 53.3, 52.5, 52. 0,52.0,51.7,40.6,38.8,32.1,32.0,30.2,27.5,26.9,24.8,23.1,21.9,21.8;

[0308] HR-MS(ESI)m / z calcd for C 24 H 43 N3O8Na + [M+Na] + 524.2942, found 524.2943.

[0309] Example 37: Electrochemical synthesis of compound 39b

[0310]

[0311] Using 39a (0.2 mmol) as starting material, according to the method and reaction conditions of Example 20, 39b was prepared as a colorless liquid in a yield of 52%.

[0312] The characterization data of compound 39b are as follows: 1 HNMR (400MHz, CDCl3) δ = 7.35 (d, J = 8.1Hz, 1H), 6.95 (d, J = 7.9Hz, 1H), 6.52 (d, J = 7.7Hz,1H),5.72-5.58(m,1H),5.13-5.02(m,2H),4.60-4.52(m,1H),4.48-4.37( m,2H),3.70(s,3H),3.60(t,J=5.9Hz,2H),2.59-2.46(m,2H),1.90-1.79(m,1H), 1.72-1.50(m,6H),1.44-1.37(m,2H),1.19(s,9H),0.90(dd,J=13.2,5.8Hz,6H);

[0313] 13 C NMR (100MHz, CDCl3)δ=179.2,172.6,172.0,171.9,132.3,119.2,62.3,53 .2,52.4,52.0,40.6,38.9,36.3,32.5,32.1,27.5,24.9,23.1,21.9,21.8;

[0314] HR-MS(ESI)m / z calcd for C 23 H 41 N3O6Na + [M+Na] + 478.2888, found 478.2881.

[0315] Example 38: Electrochemical synthesis of compound 40b

[0316]

[0317] Using 40a (0.2 mmol) as starting material, according to the method and reaction conditions of Example 20, 40b was prepared as a white solid in a yield of 52%.

[0318] The characterization data of compound 40b are as follows: 1HNMR(400MHz, CDCl3)δ=7.67(d,J=8.6Hz,1H),7.60(d,J=7.4Hz,1H),7.20(d,J=7.9Hz,1H), 6.60(d,J=7.0Hz,1H),5.78-5.64(m,1H),5.15-5.02(m,2H),4.79-4.64(m,1H),4.65-4.41( m,3H),3.70(s,3H),3.59(t,J=6.2Hz,2H),2.61-2.40(m,2H),1.89-1.77(m,1H),1.72-1.49 (m,6H),1.44-1.36(m,2H),1.31(d,J=6.9Hz,3H),1.18(s,9H),0.91(dd,J=7.6,5.6Hz,6H);

[0319] 13 C NMR (100MHz, CDCl3)δ=179.0,172.4,172.3,172.0,171.7,132.5,119.0,62.3,53.1,52 .4,52.2,51.9,48.7,41.6,38.8,36.3,33.0,32.1,27.5,24.9,23.1,22.0,21.7,18.6;

[0320] HR-MS(ESI)m / z calcd for C 26 H 46 N4O7Na + [M+Na] + 549.3259, found 549.3256.

[0321] Example 39: Electrochemical synthesis of compound 41b

[0322]

[0323] Using 41a (0.2 mmol) as starting material, according to the method and reaction conditions of Example 20, 41b was prepared as a colorless liquid with a yield of 47%.

[0324] The characterization data of compound 41b are as follows: 1HNMR (400MHz, CDCl3) δ = 7.08 (t, J = 6.0Hz, 1H), 6.47 (d, J = 7.8Hz, 1H), 4.46- 4.37(m,1H),3.65(s,3H),3.60(t,J=6.2Hz,2H),3.37-3.03(m,2H),2.25(d, J=6.7Hz,2H),2.17-2.05(m,1H),1.89-1.75(m,1H),1.70-1.50(m,4H),1.4 4-1.35(m,2H),1.18(s,9H),1.17-1.04(m,2H),0.86(dd,J=9.3,6.6Hz,6H);

[0325] 13 C NMR (100MHz, CDCl3) δ=178.9,173.8,172.4,62.2,53.0,51.8,42.9,41.6,38.9,37.3,33.2,32.5,32.1,27.6,25.2,22.8,22.7,21.9;

[0326] HR-MS(ESI)m / z calcd for:C 20 H 39 N2O5[M+H] + 387.2853, found 387.2847.

[0327] Example 40: Electrochemical synthesis of compound 42b

[0328]

[0329] Using 42a (0.2 mmol) as starting material, according to the method and reaction conditions of Example 20, 42b was prepared as a white solid in a yield of 69%.

[0330] The characterization data of compound 42b are as follows: 1 HNMR (400MHz, CDCl3) δ = 6.47 (d, J = 7.8Hz, 1H), 6.19 (s, 1H), 4.35-4.27 (m, 1H), 3.61 (t, J = 6.3Hz, 2H), 2.09-2.03 (m ,3H),1.99-1.93(m,6H),1.84-1.73(m,1H),1.68-1.63(m,6H),1.62-1.51(m,3H),1.43-1.32(m,2H),1.18(s,9H);

[0331] 13C NMR (100MHz, CDCl3) δ = 178.7, 171.0, 62.3, 53.2, 52.2, 41.6, 38.8, 36.4, 32.6, 32.2, 29.5, 27.6, 21.7;

[0332] HR-MS(ESI)m / z calcd for C 21 H 36 N2O3Na + [M+Na] + 387.2618, found 387.2615.

[0333] Example 41: Electrochemical synthesis of compound 43b

[0334]

[0335] Using 43a (0.2 mmol) as starting material, according to the method and reaction conditions of Example 20, 43b was prepared as a colorless liquid with a yield of 45%.

[0336] The characterization data of compound 43b are as follows: 1 HNMR(400MHz, CDCl3)δ=7.44(t,J=5.9Hz,1H),6.59(d,J=7.8Hz,1H),5.33(t,J=5.9Hz,1H),4.47-4.36(m,1H),3 .60(t,J=6.5Hz,2H),3.45-3.19(m,4H),1.88-1.74(m,1H),1.73-1.49(m,3H),1.46-1.37(m,11H),1.18(s,9H);

[0337] 13 C NMR (100MHz, CDCl3) δ=179.0,172.8,156.7,79.7,62.1,53.0,40.4,40.1,38.8,32.6,31.9,28.5,27.6,21.8;

[0338] HR-MS(ESI)m / z calcd for C 18 H 35 N3O5Na + [M+Na] + 396.2469, found 396.2465.

[0339] Example 42: Electrochemical synthesis of compound 44b

[0340]

[0341] Using 44a (0.2 mmol) as starting material, according to the method and reaction conditions of Example 20, 44b was prepared as a colorless liquid with a yield of 61%.

[0342] The characterization data of compound 44b are as follows: 1 HNMR(400MHz, CDCl3)δ=6.17(d,J=7.5Hz,1H),4.60-4.52(m,1H),4.44-4.36(m,1H),4.31-4.23(m,1H),3.62(t,J=6.1H z,2H),2.74(t,J=6.2Hz,2H),1.94-1.84(m,1H),1.80-1.69(m,1H),1.64-1.52(m,2H),1.49-1.38(m,2H),1.20(s,9H);

[0343] 13 C NMR (100MHz, CDCl3) δ = 178.8, 172.4, 116.8, 62.2, 59.5, 52.2, 38.8, 32.0, 27.5, 21.8, 18.1;

[0344] HR-MS(ESI)m / z calcd for C 14 H 24 N2O4Na + [M+Na] + 307.1629, found 307.1622.

[0345] Example 43: Electrochemical synthesis of compound 45b

[0346]

[0347] Using 45a (0.2 mmol) as starting material, according to the method and reaction conditions of Example 20, 45b was prepared as a colorless liquid with a yield of 47%.

[0348] The characterization data of compound 45b are as follows: 1 HNMR (400MHz, CDCl3) δ = 6.23 (d, J = 7.7Hz, 1H), 4.96 (d, J = 13.3Hz, 2H), 4.68-4.47 (m, 3H), 3.67- 3.56(m,2H),1.91-1.84(m,1H),1.75(s,3H),1.75-1.50(m,3H),1.48-1.35(m,2H),1.20(s,9H);

[0349] 13C NMR (100MHz, CDCl3) δ = 178.6, 172.7, 139.4, 113.8, 68.8, 62.4, 52.0, 38.9, 32.5, 32.1, 27.6, 21.6, 19.6;

[0350] HR-MS(ESI)m / z calcd for C 15 H 27 NO4Na + [M+Na] + 308.1832, found 308.1827.

[0351] Example 44 Reaction effect of compound 1a under different conditions

[0352] (1) Different additives shown in Table 1 were added to the electrolyte, and compound 1b was prepared according to the method of Example 1. The yields are shown in Table 1.

[0353]

[0354] Table 1

[0355]

[0356]

[0357] (2) Compound 1b was prepared according to the method of Example 1 using different solvents shown in Table 2. The yields are shown in Table 2.

[0358]

[0359] Table 2

[0360]

[0361] (3) Compound 1b was prepared by using different electrodes and electrolytes shown in Table 3 according to the method of Example 1. The yields are shown in Table 3.

[0362]

[0363] Table 3

[0364]

[0365]

[0366] Note: C = graphite flake, RVC = reticulated glassy carbon.

[0367] (4) Compound 1b was prepared according to the method of Example 1 using different currents shown in Table 4. The yields are shown in Table 4.

[0368]

[0369]

[0370] Example 45 Reaction effect of compound 23a under different conditions

[0371] Compound 23b was prepared according to the method of Example 21 under the conditions shown in Table 5. The yield is shown in Table 5.

[0372]

[0373] Table 5

[0374]

[0375] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for synthesizing a distal amino alcohol compound, It is characterized in that The steps include: Electrolyzing the cyclic amine compound represented by formula (I) to obtain the distal amino alcohol compound represented by formula (II), Among them, R 1 Selected from: aryl, arylformyl, alkylacyl; Each R 2 are independently selected from: hydrogen, alkoxy, halogen, aryl, alkyl, alkoxycarbonyl, or two adjacent R 2 Together with the carbon atom to which it is attached, it forms a cycloalkyl group; R is selected from: hydrogen, alkoxy, halogen, aryl, alkyl, Each R 3 are independently selected from: a group after an amino hydrogen is removed from an amino acid or its ester, a group after an amino hydrogen is removed from a dipeptide or its ester, a group after an amino hydrogen is removed from a tripeptide or its ester, R 4 Substituted or unsubstituted alkylamino, R 4 Substituted or unsubstituted cycloalkylamino, R 4 Substituted or unsubstituted alkoxy, R 4 a substituted or unsubstituted cycloalkoxy group; Each R 4 Each of the following is independently selected from the group consisting of: amino, protected amino, cyano, alkenyl, and alkoxycarbonyl; R 5 Selected from: hydrogen, methyl, ethyl; R 6 Selected from: hydrogen, methoxy, ethoxy; n is selected from: 0, 1, 2, 3, 4; m is selected from: 0, 1, 2, 3, 4, 5, 6.

2. The method for synthesizing the distal amino alcohol compound according to claim 1, It is characterized in that The cyclic amine compound has a structure shown in the following formula (III): The distal amino alcohol compound has a structure shown in the following formula (IV): n is selected from: 0, 1, 2, 3, 4; m is selected from: 0, 1, 2, 3.

3. The method for synthesizing the distal amino alcohol compound according to claim 1, It is characterized in that The cyclic amine compound has a structure as shown in the following formula (V): The distal amino alcohol compound has a structure shown in the following formula (VI): n is selected from: 1, 2, 3.

4. A method for synthesizing a distal amino alcohol compound according to any one of claims 1 to 3, It is characterized in that R 1 Selected from: C 6 -C 10 Aryl, C 6 -C 10 Arylformyl, C 1 -C 12 Alkyl acyl; Preferably, R 1 Selected from: phenyl, benzoyl, C 1 -C 6 Alkyl acyl; Preferably, R 1 Selected from: phenyl, benzoyl, pivaloyl.

5. The method for synthesizing the distal amino alcohol compound according to claim 1 or 2, It is characterized in that Each R 2 are independently selected from: hydrogen, C 1 -C 12 Alkoxy, halogen, C 6 -C 10 Aryl, C 1 -C 12 Alkyl, C 1 -C 12 Alkoxycarbonyl, or two adjacent R 2 Together with the carbon atom to which it is attached, it forms C 3 -C 12 Cycloalkyl; Preferably, each R 2 are independently selected from: hydrogen, C 1 -C 6 Alkoxy, halogen, C 6 -C 10 Aryl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxycarbonyl, or two adjacent R 2 Together with the carbon atom to which it is attached, it forms C 3 -C 8 Cycloalkyl; Preferably, each R 2 are independently selected from: hydrogen, C 1 -C 3 Alkoxy, halogen, phenyl, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxycarbonyl, or two adjacent R 2 Together with the carbon atom to which it is attached, it forms C 3 -C 6 Cycloalkyl; Preferably, each R 2 are independently selected from: hydrogen, methoxy, fluorine, phenyl, chlorine, methyl, methoxycarbonyl, or two adjacent R 2 Together with the carbon atom to which it is connected, it forms a cyclopropyl or cyclopentyl group.

6. The method for synthesizing the distal amino alcohol compound according to claim 1 or 3, It is characterized in that R is selected from: hydrogen, C 1 -C 12 Alkoxy, halogen, C 6 -C 10 Aryl, C 1 -C 12 alkyl, Each R 3 are independently selected from: a group after an amino hydrogen is removed from an amino acid or its ester, a group after an amino hydrogen is removed from a dipeptide or its ester, a group after an amino hydrogen is removed from a tripeptide or its ester, R 4 Substituted or unsubstituted C 1 -C 12 Alkylamino, R 4 Substituted or unsubstituted C 3 -C 12 Cycloalkylamino, R 4 Substituted or unsubstituted C 1 -C 12 Alkoxy, R 4 Substituted or unsubstituted C 3 -C 12 Cycloalkoxy; Each R 4 are independently selected from: amino, protected amino, cyano, alkenyl, C 1 -C 12 Alkoxycarbonyl; Preferably, R is selected from: hydrogen, methoxy, fluorine, phenyl, chlorine, methyl, methoxycarbonyl, or a group selected from the following structures:

7. The method for synthesizing the distal amino alcohol compound according to claim 1, It is characterized in that The cyclic amine compound is selected from the following compounds: The distal amino alcohol compound is selected from the following compounds:

8. A method for synthesizing a distal amino alcohol compound according to any one of claims 1 to 3, It is characterized in that The electrolysis is carried out in a single-chamber electrolytic cell containing an electrolyte; Preferably, the solvent in the electrolyte is water, methanol, ethanol, acetone, or a mixed solvent of acetone and water; Preferably, the electrolyte in the electrolyte is one or more of tetrabutylammonium hydrogen sulfate, ammonium sulfate and tetrabutylammonium perchlorate; Preferably, a copper compound is added to the electrolyte; Preferably, the volume ratio of acetone to water in the mixed solvent of acetone and water is 1:1-8, preferably 1:6-8.

9. The method for synthesizing the distal amino alcohol compound according to claim 8, It is characterized in that R 5 and R 6 are all hydrogen, and the solvent in the electrolyte is water, or a mixed solvent of acetone and water; or, R 5 is methyl, R 6 is a methoxy group, and the solvent in the electrolyte is methanol; or R 5 Ethyl, R 6 The solvent in the electrolyte is ethanol.

10. The method for synthesizing the distal amino alcohol compound according to claim 8, It is characterized in that The molar ratio of the cyclic amine compound to the electrolyte is 1:0.5-1.5, preferably 1:0.8-1.2; and / or, The molar concentration of the electrolyte in the electrolyte solution is 0.02 mmol / mL-0.08 mmol / mL, preferably 0.04 mmol / mL-0.06 mmol / mL; and / or, The copper compound is one or more of tetraacetonitrile copper tetrafluoroborate, tetraacetonitrile copper hexafluorophosphate, copper trifluoromethanesulfonate, cupric chloride, cuprous chloride, cupric bromide and cuprous iodide; and / or, The molar ratio of the cyclic amine compound to the copper compound is 1:0.1-0.8, preferably 1:0.2-0.5; and / or, The molar concentration of the copper compound in the electrolyte is 0.004 mmol / mL-0.04 mmol / mL, preferably 0.01 mmol / mL-0.025 mmol / mL; and / or, The anode for electrolysis is a graphite sheet or carbon felt, and the cathode is a graphite sheet, carbon felt, platinum sheet or copper sheet; and / or, The electrolysis is performed using a constant current, the current intensity is 4 mA to 30 mA, and the amount of current is 4.5 F / mol to 34 F / mol based on the amount of the cyclic amine compound; The electrolysis temperature is 20°C-30°C; Preferably, the current intensity is 8 mA to 20 mA, and the amount of current applied is 8.9 F / mol to 22.5 F / mol based on the amount of the cyclic amine compound.

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