Method for synthesis of amide compounds mediated by acid / sulfate / peroxodisulfate under electrochemical conditions

Abstract

The present application relates to a method for synthesizing amide compounds under the mediation of acid / sulfate / peroxydisulfate in electrochemical conditions, and belongs to the field of electrochemical synthesis, comprising the following steps: (1) adding acid / sulfate / peroxydisulfate into an electrolytic cell containing a hydrocarbon compound, an electrolyte and a nitrile solvent, assembling an anode and a cathode, electrolyzing to obtain an alkyl carbonium ion, and then performing a Ritter type amination reaction to obtain a nitrilium cation intermediate; (2) after the reaction is completed, slowly adding a saturated NaHCO3 solution into the electrolytic cell to perform a hydrolysis reaction, and obtaining an amide compound. The present application provides an electrochemical preparation method for amide compounds, avoids the use of metal catalysts, expensive selective fluorine reagents and high-valence iodine reagents, has the advantages of wide substrate applicability, green efficiency, high atom economy and the like, can be used for the synthesis of key intermediates of drug amantadine hydrochloride and memantine hydrochloride, and has certain practical application value.

Description

Technical Field

[0001] This invention belongs to the field of electrochemical synthesis technology, specifically relating to the realization of unactivated C(sp) under electrochemical and sulfate reaction systems. 3 Ritter-type amination reactions of the )-H bond, involving the synthesis of key intermediates of the drugs memantine hydrochloride and amantadine hydrochloride. Background Technology

[0002] Amine compounds are widely found in natural products, agrochemicals, pharmaceuticals, and organic materials. The construction of C(sp) bonds has always been a hot topic in organic synthesis research, due to the fact that C(sp) bonds are widely distributed in organic products. 3 )-H is characterized by low reactivity and poor selectivity, C(sp 3 The direct amination of H-H is very challenging.

[0003] Typically, only relatively active C(sp) can be achieved through direct or indirect anodizing. 3 Amination reactions of the )-H bond, including heteroatoms, carbonyl α-positions, allylic positions, and benzylic positions of C(sp) 3 The -H bond has limited substrate applicability and cannot be applied to C(sp) bonds in inert alkanes. 3 Amination reactions involving the )-H bonds. In addition, Baran et al.'s group reported several Ritter-type amination reactions, which are inert C(sp) bonds. 3 Amination of the -H bond provides an effective method (J. Am. Chem. Soc. 2012, 134, 2547-2550; J. Am. Chem. Soc. 2021, 143, 8597-8602.). However, these works cannot avoid the use of stoichiometric, expensive oxidizing agents, such as selective fluorine reagents and high-valent iodine reagents. Summary of the Invention

[0004] Based on the limitations of the above reaction systems, we developed a sulfate-mediated Ritter-type C(sp3)-H amination reaction system under electrochemical conditions. This system uses readily available and inexpensive sulfate as the pre-oxidant, avoiding the use of stoichiometric oxidants and metal catalysts. It boasts advantages such as broad substrate applicability, green and efficient operation, and high atom economy. It can be used for the synthesis of key intermediates in the pharmaceuticals memantine hydrochloride and amantadine hydrochloride, demonstrating significant practical application value.

[0005] The specific solution adopted in this invention is as follows:

[0006] In a first aspect, the present invention provides a method for synthesizing amide compounds mediated by acid / sulfate / persulfate under electrochemical conditions, comprising the following steps:

[0007] (1) Add acid / sulfate / persulfate to an electrochemical reaction device containing hydrocarbon substrate, electrolyte and nitrile solvent, assemble anode and cathode, electrolyze to obtain alkyl carbocations, and then carry out Ritter-type reaction steps to obtain nitrile onion intermediate;

[0008] (2) After the reaction in step (1) is completed, saturated NaHCO3 aqueous solution is slowly added dropwise to the electrochemical reaction device to carry out hydrolysis reaction and obtain amide compounds.

[0009] The reaction route is as follows:

[0010]

[0011] Among them, R 1 and R 2 It is an alkyl group or H; R 3 It can be alkyl, aryl, or heterocyclic.

[0012] According to a preferred embodiment of the present invention, the acid is one or any combination of sulfuric acid, methanesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid, and is used in an amount of 2-16 equivalents. The persulfate is one or any combination of sodium persulfate, potassium persulfate, and ammonium persulfate, and is used in an amount of 1-8 equivalents. The sulfate is one or any combination of sodium sulfate, potassium sulfate, and ammonium sulfate, and is used in an amount of 2-16 equivalents.

[0013] According to a preferred embodiment of the present invention, the nitrile is one or any combination of acetonitrile, deuterated acetonitrile, butyronitrile, isobutyronitrile, ethyl cyanoacetate, and adiponitrile.

[0014] According to a preferred embodiment of the present invention, the electrolyte is one or any combination of quaternary ammonium perchlorate, quaternary ammonium tetrafluoroborate, quaternary ammonium hexafluorophosphate, quaternary ammonium trifluoromethanesulfonate, lithium perchlorate, and lithium tetrafluoroborate, and the amount used is 0.1M.

[0015] According to a preferred embodiment of the present invention, in the synthesis method, the concentration of the substrate is 0.05-0.5 mol / L.

[0016] According to a preferred embodiment of the present invention, in step (1), the anode material is one or any combination of platinum, graphite, carbon fiber, carbon felt, carbon paper, glassy carbon, foamed glassy carbon, and conductive glass, with platinum being the most preferred. The cathode material is one or any combination of platinum, nickel, graphite, carbon fiber, carbon felt, carbon paper, glassy carbon, foamed glassy carbon, and conductive glass, with platinum being the most preferred.

[0017] According to a preferred embodiment of the present invention, in step (1), the electrolysis method can be constant current electrolysis or constant voltage electrolysis. The current density of constant current electrolysis is 2mA / mmol-20mA / mmol, preferably 5mA / mmol-10mA / mmol; the voltage of constant voltage electrolysis is 2V-10V, preferably 3V-6V.

[0018] According to a preferred embodiment of the present invention, in step (1), the reaction temperature is 0-40°C, preferably 20-30°C.

[0019] According to a preferred embodiment of the present invention, in step (1), the amount of electricity used is 2-10 F / mol, preferably 4-8 F / mol.

[0020] According to a preferred embodiment of the present invention, the electrolytic cell is a diaphragmless electrolytic cell or a partitioned electrolytic cell.

[0021] Secondly, the present invention also provides the above synthesis method (Ritter type C(sp) 3 Application of the )-H amination reaction system in the preparation of key intermediates for the drugs memantine hydrochloride and amantadine hydrochloride.

[0022] Compared with the prior art, the method for synthesizing amide compounds provided by the present invention has the following beneficial effects:

[0023] 1. The raw materials are widely available, inexpensive, and commercially available on a large scale, eliminating the need for multi-step preparation and synthesis;

[0024] 2. Using sulfate as the pre-oxidant, the amount used is relatively small, and there is no need to use expensive oxidants, precious metal catalysts, etc., resulting in low reaction cost;

[0025] 3. Electrolysis replaces oxidants and reducing agents, avoiding the application of stoichiometric oxidants. The reaction system is simple, environmentally friendly, has high production efficiency, and low emissions of waste.

[0026] 4. Replacing the traditional multi-step synthesis method with a one-step method greatly simplifies the operation process and significantly improves the overall yield. Detailed Implementation

[0027] The technical concept of this invention is to prepare amide compounds using an electrochemical method, wherein the preparation process is mediated by sulfate ions under electrochemical conditions, resulting in the release of unactivated C(sp) compounds. 3 The Ritter-type amination reaction of the -H bond is described below:

[0028]

[0029] In this case, R1 and R2 are hydrogen or alkyl, and R3 is alkyl, aryl or heterocyclic.

[0030] Specifically, it includes two steps:

[0031] (1) Add acid / sulfate / persulfate dropwise into an electrochemical reaction apparatus containing substrate, electrolyte and nitrile solvent, and electrolyze under constant current or constant voltage to prepare nitrile onion intermediate;

[0032] (2) After the reaction in step (1) is completed, saturated aqueous solution of NaHCO3 is slowly added dropwise to the electrochemical reaction device to carry out hydrolysis reaction and neutralize excess acid to obtain amide compounds.

[0033] The acid is one or more of sulfuric acid, methanesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid, used in an amount of 2-16 equivalents. The persulfate is one or more of sodium persulfate, potassium persulfate, and ammonium persulfate, used in an amount of 1-8 equivalents. The sulfate is one or more of sodium sulfate, potassium sulfate, and ammonium sulfate, used in an amount of 2-16 equivalents.

[0034] The nitrile is one or any combination of acetonitrile, deuterated acetonitrile, butyronitrile, isobutyronitrile, ethyl cyanoacetate, and adiponitrile.

[0035] The electrolyte is one or any combination of quaternary ammonium perchlorate, quaternary ammonium tetrafluoroborate, quaternary ammonium hexafluorophosphate, quaternary ammonium trifluoromethanesulfonate, lithium perchlorate, and lithium tetrafluoroborate, and is used in an amount of 0.1 M.

[0036] In the synthesis method, the concentration of the substrate is 0.05-0.5 mol / L.

[0037] In step (1), the anode material is one or more of platinum, graphite, carbon fiber, carbon felt, carbon paper, glassy carbon, foamed glassy carbon, and conductive glass, with platinum being the most preferred. The cathode material is one or more of platinum, nickel, graphite, carbon fiber, carbon felt, carbon paper, glassy carbon, foamed glassy carbon, and conductive glass, with platinum being the most preferred.

[0038] In step (1), the electrolysis method can be constant current or constant voltage electrolysis. The current density for constant current electrolysis is 2mA / mmol-20mA / mmol, preferably 5mA / mmol-10mA / mmol; the voltage for constant voltage electrolysis is 2V-10V, preferably 3V-6V.

[0039] In step (1), the reaction temperature is 0-40℃, preferably 20-30℃.

[0040] In step (1), the amount of electricity used is 2-10 F / mol, preferably 4-8 F / mol.

[0041] The electrochemical reaction device is an electrolytic cell, which is either a diaphragmless electrolytic cell or a partitioned electrolytic cell.

[0042] The present invention will be further described in detail below through specific embodiments.

[0043] In the following embodiments, unless otherwise specified, the techniques or conditions described in the literature in this field or the product instructions shall be followed; if the manufacturers of the reagents or instruments used are not specified, they are all conventional products that can be purchased.

[0044] Example 1

[0045]

[0046] Electrolytes tetrabutylammonium tetrafluoroborate (109.76 mg, 0.1 M), 1,3-dimethyladamantane (82 mg, 0.5 mmol), and acetonitrile (3 mL) were added to the electrochemical reaction apparatus. Sulfuric acid (108 μL, 2 mmol) was slowly added dropwise. The mixture was stirred at 25 °C and electrolyzed at a constant current of 5 mA for 24 hours, with a power consumption of 4.4 F / mol.

[0047] After the reaction is complete, slowly add a saturated NaHCO3 solution dropwise into the reaction system until no more bubbles are generated.

[0048] The reaction mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed with water (10 mL) and saturated brine (10 mL), respectively, and then dried over anhydrous Na₂SO₄. The organic solvent was removed by vacuum distillation. The concentrate was purified by silica gel column chromatography to obtain the high-purity final product 1-acetamido-3,5-dimethyladamantane, which is a white crystal with an overall yield of 93%.

[0049] The following are the 1H NMR, 1C NMR, and 1M NMR data of the product, which indicate that the product obtained is 1-acetamido-3,5-dimethyladamantane.

[0050] White solid, 1 H NMR(400MHz,Chloroform-d)δ5.26(d,J=23.4Hz,1H),2.11(hept,J=3.2Hz,1H),1.88(s,3H),1.83–1.78(m ,2H),1.67–1.56(m,4H),1.36(dt,J=12.3,2.7Hz,2H),1.30–1.23(m,2H),1.20–1.07(m,2H),0.83(s,6H). 13C NMR (101MHz, Chloroform-d) δ169.54,53.34,50.57,47.46(×2),42.64(×2),40.02,32.26(×2),30.05(×2),30.03,24.51.HRMS(EI):exact mass calculated for C 14 H 23 NO[M] + require m / z=221.1780, found m / z=221.1778.

[0051] Example 2-10

[0052] The method described in Example 1 was modified by using a different pre-oxidant and different acids / sulfates / persulfates for the reaction. The reaction results are shown in Table 1 below.

[0053] Table 1

[0054] Example Pre-oxidant Yield (%) 2 mesylate 89 3 Trifluoroacetic acid 88 4 Trifluoromethanesulfonic acid 91 5 Sodium sulfate 86 6 potassium sulfate 84 7 ammonium sulfate 85 8 Sodium persulfate 88 9 Potassium persulfate 90 10 ammonium persulfate 91

[0055] In Examples 2-10, different pre-oxidants were used, and they were all applied well to the reaction, achieving good yields.

[0056] Examples 11-15

[0057] The method described in Example 1 was used, except that a different electrolyte was used. The reaction results are shown in Table 2 below.

[0058] Table 2

[0059] Example electrolytes Yield (%) 11 Tetrabutylammonium perchlorate 86 12 Tetrabutylhexammonium phosphate 85 13 Tetrabutyltrifluoromethanesulfonate ammonium 83 14 Lithium perchlorate 82 15 Lithium tetrafluoroborate 80

[0060] In Examples 1-15, different electrolytes were used, and all of them were applied well to the reaction and achieved good yields, but the electrolyte in Example 1 had the best effect.

[0061] Examples 16-17

[0062] The method described in Example 1 was used, except that a different substrate concentration was used. The reaction results are shown in Table 3 below.

[0063] Table 3

[0064] Example substrate concentration Yield (%) 16 0.05M 86 17 0.5M 89

[0065] In Examples 16-17, different substrate concentrations were used, and all of them were applied well to the reaction and achieved good yields. However, the substrate concentration in Example 1 was the most effective.

[0066] Examples 18-32

[0067] The method described in Example 1 was followed, except that different anode and cathode materials were used. The reaction results are shown in Table 4 below.

[0068] Table 4

[0069] Example Anode material - Cathode material Yield (%) 18 Graphite-Platinum 67 19 carbon fiber-platinum 68 20 Carbon felt-platinum 64 21 Carbon paper-platinum 58 22 Glassy carbon-platinum 59 23 Foamed glassy carbon-platinum 63 24 Conductive glass-platinum 59 25 Platinum-nickel 63 26 Platinum-graphite 71 27 Platinum-carbon fiber 74 28 Platinum-carbon felt 78 29 Platinum-carbon paper 64 30 Platinum-glass carbon 75 31 Platinum-foamed glassy carbon 60 32 Platinum-conductive glass 72

[0070] In Examples 18-32, different anode and cathode materials were used, all of which could be applied to the reaction, but the electrode material in Example 1 was the most effective.

[0071] Examples 33-37

[0072] The method described in Example 1 is different from using different current densities or voltages. The reaction results are shown in Table 5 below.

[0073] Table 5

[0074] Example Current density / voltage Yield (%) 33 2mA / mmol 84 34 20mA / mmol 82 35 2V 85 36 5V 90 37 10V 82

[0075] In Examples 33-37, different current densities or voltages were used, and all of them were applied well to the reaction, achieving good yields. However, the current density in Example 1 was the most effective.

[0076] Examples 38-39

[0077] The method described in Example 1 was followed, except that a different reaction temperature was used. The reaction results are shown in Table 6 below.

[0078] Table 6

[0079] Example temperature Yield (%) 38 0℃ 88 39 40℃ 85

[0080] In Examples 38-39, different reaction temperatures were used, and all of them were applied well to the reaction, achieving good yields. However, the reaction temperature in Example 1 was the most effective.

[0081] Examples 40-41

[0082] The method described in Example 1 was followed, except that a different amount of electricity was used. The reaction results are shown in Table 7 below.

[0083] Table 7

[0084] Example Electricity consumption Yield (%) 40 2F / mol 67 41 10F / mol 86

[0085] In Examples 40-41, different amounts of electricity were used, and all of them were applied well to the reaction and achieved good yields, but the amount of electricity used in Example 1 was the most effective.

[0086] Example 42

[0087] The method described in Example 1 is different except that a partitioned electrolytic cell is used, and the reaction yield is 85%, which can be well applied to the reaction. However, the electrolytic cell in Example 1 has the best effect.

[0088] Examples 43-47

[0089] The method described in Example 1 was followed, except that a different solvent was used. The reaction results are shown in Table 8 below.

[0090] Table 8

[0091]

[0092] In Examples 43-47, different solvents were used, and different amide products were obtained in good yields.

[0093] Examples 48-68

[0094] The method described in Example 1 was followed, except that a different substrate was used. The reaction results are shown in Table 9 below.

[0095] Table 9

[0096]

[0097]

[0098] In Examples 48-68, different substrates were used, and different amide products were obtained in good yields.

[0099] It should be noted that the above-described embodiments should be understood as illustrative, not as limiting the scope of protection of this invention. The scope of protection of this invention is defined by the claims. For those skilled in the art, some non-essential improvements and adjustments made to this invention without departing from the essence and scope of this invention still fall within the scope of protection of this invention.

Claims

1. A method for synthesizing sulfate / persulfate-mediated amide compounds under electrochemical conditions, characterized in that, The synthesis method includes the following steps: (1) Sulfate / persulfate is added to an electrochemical reaction apparatus containing a compound substrate, an electrolyte and a nitrile solvent. The anode and cathode are assembled and electrolyzed to obtain alkyl carbocations. Then, a Ritter-type reaction step is carried out to obtain a nitrile onium ion intermediate. (2) After the reaction in step (1) is completed, saturated NaHCO3 aqueous solution is slowly added dropwise to the electrochemical reaction apparatus to carry out hydrolysis reaction and obtain amide compounds. The reaction route is as follows: ， Among them, R 1 and R 2 It is an alkyl group or H; R 3 It is an alkyl, aryl, or heterocyclic group; The persulfate is one or more of sodium persulfate, potassium persulfate, and ammonium persulfate, and is used in an amount of 1-8 equivalents; the sulfate is one or more of sodium sulfate, potassium sulfate, and ammonium sulfate, and is used in an amount of 2-16 equivalents. The nitrile is acetonitrile; The electrolyte is one or any combination of quaternary ammonium perchlorate, quaternary ammonium tetrafluoroborate, quaternary ammonium hexafluorophosphate, quaternary ammonium trifluoromethanesulfonate, lithium perchlorate, and lithium tetrafluoroborate, and is used in an amount of 0.1 M.

2. The synthesis method according to claim 1, characterized in that, In the synthesis method, the concentration of the substrate is 0.05-0.5 M.

3. The synthesis method as described in claim 1, characterized in that, The anode material is one or any of the following: platinum, graphite, carbon fiber, carbon felt, carbon paper, glassy carbon, foamed glassy carbon, and conductive glass; the cathode material is one or any of the following: platinum, nickel, graphite, carbon fiber, carbon felt, carbon paper, glassy carbon, foamed glassy carbon, and conductive glass.

4. The synthesis method according to claim 1, characterized in that: In step (1), the electrolysis method is constant current or constant voltage electrolysis. The current intensity of constant current electrolysis is 2 mA / mmol-20 mA / mmol; the voltage of constant voltage electrolysis is 2 V-10 V.

5. The synthesis method according to claim 1, characterized in that, In step (1), the reaction temperature is 0-40℃ and the electricity consumption is 2-10 F / mol.

6. The synthesis method according to claim 1, characterized in that, The electrochemical reaction device is an electrolytic cell, which is either a diaphragmless electrolytic cell or a partitioned electrolytic cell.

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