A method for synthesizing nitrosamine organic compounds

Abstract

The present invention discloses a method for synthesizing a nitrosamine organic compound. The method comprises reacting a compound having a structure represented by formula (I) with nitromethane under electrochemical action to obtain a nitrosamine organic compound having a structure represented by formula (II). The method achieves nitrosation of a secondary amine through a one-step reaction under mild reaction conditions. The obtained product has a high reaction yield and is valuable for reuse as a pharmaceutical. This method therefore has excellent application prospects.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing nitrosamine organic compounds. Background Art

[0002] Nitrosamine compounds (NOCs) are widely present in a variety of natural products and synthetic drugs, including L-alanine, formosterine, and streptozotocin. Nitrosylated derivatives of certain drugs also have important pharmaceutical value, such as Form Desloratadine, an antihistamine used to relieve systemic and local symptoms of chronic idiopathic urticaria and perennial allergic rhinitis. In addition to their important biomedical applications, NOCs are also important intermediates in organic synthesis, facilitating the preparation of hydrazines and nitro compounds. Consequently, significant attention has been paid to the synthesis of NOCs, leading to the development of a growing number of methods.

[0003] The traditional synthesis of NOCs involves N-nitrosation of secondary amines. The most commonly used nitrosation reagents include sodium nitrosodisulfonate (NaNO2), tert-butyl nitrite (TBN), fremi salt (dipotassium nitrosodisulfonate), nitrous peroxide, and bis(triphenylphosphinilidene)ammonium nitrite. However, these methods require the use of large amounts of metals or chemical oxidants, and most reagents are flammable and explosive. Furthermore, the substrates are limited to aromatic secondary amines. Therefore, there is a need for more environmentally friendly and efficient methods to synthesize alkyl nitrosamines.

[0004] Organic electrochemistry is currently considered an environmentally friendly, sustainable, and green synthesis method, avoiding the use of oxidants through electron transfer between electrodes and substrates or catalysts. Several electrochemical methods for the synthesis of NOCs have been reported, but these methods often use nitrosating agents that are flammable and explosive, require metal catalysis, or react in an inert atmosphere. These conditions are relatively stringent, resulting in generally low to moderate yields.

[0005] We have long focused on halogen-mediated electrochemical organic synthesis. Furthermore, we have studied the reactivity of nitromethane under electrocatalysis and achieved some remarkable results. Building on this, we have designed an electrochemical method for the synthesis of NOCs using nitromethane as a nitrosating agent and secondary amines as reactants under catalyst-free conditions. Summary of the Invention

[0006] In view of this, the present invention provides a method for synthesizing nitrosamine organic compounds. This method can nitrosate secondary amines using nitromethane under mild electrochemical conditions to obtain nitrosamine compounds with high reaction yield.

[0007] The method for synthesizing the nitrosamine organic compound of the present invention comprises reacting a compound having a structure represented by formula (I) with nitromethane under electrochemical action to obtain a nitrosamine organic compound having a structure represented by formula (II);

[0008]

[0009] Specifically, a compound with a structure shown in formula (I) and nitromethane are added to a solvent, and a target product with a structure shown in formula (II) is obtained through an electrochemical reaction in the presence of a catalyst and a base.

[0010] in:

[0011] R1 is selected from C1-C6 alkyl, C6-C9 aryl or substituted C6-C9 aryl, and the substituent in the substituted C6-C9 aryl is C1-C5 alkyl; R2 is selected from C1-C6 alkyl, C6-C9 aryl or substituted C6-C9 aryl, and the substituent in the substituted C6-C9 aryl is C1-C5 alkyl.

[0012] Or R1 and R2 together form a C4-C9 nitrogen-containing heterocycle or a substituted C4-C9 nitrogen-containing heterocycle, and the substituent in the substituted C4-C9 nitrogen-containing heterocycle is a C1-C6 alkyl group or a C6-C14 aryl group.

[0013] Further preferred:

[0014] R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, 3-methylpropyl, cyclopentyl, cyclohexyl, benzyl, 2-phenylethyl, 3-phenylbutyl, 4-phenylbutyl, 4-methylbenzyl, 4-ethylbenzyl, 4-propylbenzyl, 4-butylbenzyl, 2-methylbenzyl, 2-ethylbenzyl, 2-propylbenzyl, 2-butylbenzyl, 3-methylbenzyl, 3-ethylbenzyl, 3-propylbenzyl or 3-butylbenzyl; The R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, 3-methylpropyl, cyclopentyl, cyclohexyl, benzyl, 2-phenylethyl, 3-phenylbutyl, 4-phenylbutyl, 4-methylbenzyl, 4-ethylbenzyl, 4-propylbenzyl, 4-butylbenzyl, 2-methylbenzyl, 2-ethylbenzyl, 2-propylbenzyl, 2-butylbenzyl, 3-methylbenzyl, 3-ethylbenzyl, 3-propylbenzyl or 3-butylbenzyl.

[0015] Or R1 and R2 together form a C4-C6 nitrogen-containing heterocycle or a substituted C4-C6 nitrogen-containing heterocycle, wherein the C4-C9 nitrogen-containing heterocycle is pyrrole, piperidine, piperazine, morpholine, thiomorpholine, isoindoline or tetrahydroisoquinoline; and the substituent in the substituted C4-C9 nitrogen-containing heterocycle is a C1-C6 alkyl, a C1-C6 alkoxy, a halogen, a nitro or a C6-C14 aryl.

[0016] Going a step further:

[0017] The compound with the structure of formula (II) is specifically a compound represented by formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6), formula (II-7), formula (II-8) or formula (II-9).

[0018]

[0019] The molar ratio of the compound represented by formula (I) to nitromethane is 1:1-5, preferably 1:(1-3).

[0020] The reaction temperature is 0 to 80°C, preferably 40 to 65°C, and most preferably 45 to 55°C.

[0021] The catalyst is selected from one or more of potassium iodide, sodium iodide, tetramethylammonium iodide, tetraethylammonium iodide, tetrabutylammonium iodide, ammonium iodide, elemental iodine, potassium iodate, 2-iodoacylbenzoic acid, N-iodosuccinimide, and iodobenzene acetate.

[0022] The base is selected from one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, DABCO, quinoline ring, DBU, DBN, DIPEA, DMAP, triethylamine, trifluoroethanol and hexafluoroisopropanol.

[0023] The solvent is selected from one or more of toluene, xylene, chloroform, 1,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, acetone, water, tetrahydrofuran, 1,2-dichloroethane, and dichloromethane.

[0024] During the electrochemical reaction, the electrode material is selected from one or more of a carbon electrode, a platinum electrode, a nickel electrode, a zinc electrode, an iron electrode, a copper electrode, and a cobalt electrode.

[0025] Compared with the prior art, the present invention provides a method for synthesizing nitrosamine compounds. Through a one-step reaction, it is the first time to realize the method of obtaining nitrosamine compounds by using nitromethane as a nitrosating reagent to react with secondary amines under electrochemical conditions without adding an additional oxidant. The reaction conditions are mild and the reaction yield of the obtained product is high. This is a green and efficient method for synthesizing nitrosamine compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The synthetic product provided by Example 1 of the present invention 1 H NMR ( 1 H-NMR) spectrum.

[0027] Figure 2 The synthetic product provided by Example 1 of the present invention 13 C NMR ( 13 C-NMR) spectrum.

[0028] Figure 3 The synthetic product provided by Example 2 of the present invention 1 H NMR ( 1 H-NMR) spectrum.

[0029] Figure 4 The synthetic product provided by Example 2 of the present invention 13 C NMR ( 13 C-NMR) spectrum.

[0030] Figure 5 The synthetic product provided by Example 3 of the present invention 1 H NMR ( 1 H-NMR) spectrum.

[0031] Figure 6 The synthetic product provided by Example 3 of the present invention 13 C NMR ( 13 C-NMR) spectrum.

[0032] Figure 7 The synthetic product provided by Example 4 of the present invention 1 H NMR ( 1 H-NMR) spectrum.

[0033] Figure 8 The synthetic product provided by Example 4 of the present invention 13 C NMR ( 13 C-NMR) spectrum.

[0034] Figure 9 The synthetic product provided by Example 5 of the present invention 1 H NMR ( 1 H-NMR) spectrum.

[0035] Figure 10 The synthetic product provided by Example 5 of the present invention 13 C NMR ( 13 C-NMR) spectrum.

[0036] Figure 11 The synthetic product provided by Example 6 of the present invention 1 H NMR ( 1 H-NMR) spectrum.

[0037] Figure 12 The synthetic product provided by Example 6 of the present invention13 C NMR ( 13 C-NMR) spectrum.

[0038] Figure 13 The synthetic product provided by Example 7 of the present invention 1 H NMR ( 1 H-NMR) spectrum.

[0039] Figure 14 The synthetic product provided by Example 7 of the present invention 13 C NMR ( 13 C-NMR) spectrum.

[0040] Figure 15 The synthetic product provided by Example 8 of the present invention 1 H NMR ( 1 H-NMR) spectrum.

[0041] Figure 16 The synthetic product provided by Example 8 of the present invention 13 C NMR ( 13 C-NMR) spectrum.

[0042] Figure 17 The synthetic product provided by Example 9 of the present invention 1 H NMR ( 1 H-NMR) spectrum.

[0043] Figure 18 The synthetic product provided by Example 9 of the present invention 13 C NMR ( 13 C-NMR) spectrum. DETAILED DESCRIPTION

[0044] The present invention provides a method for synthesizing nitrosamine compounds, comprising:

[0045] The compound of the structure represented by formula (I) and nitromethane are reacted under electrochemical action to obtain a nitrosamine organic compound of the structure represented by formula (II);

[0046]

[0047] Wherein, R1 is selected from C1-C6 alkyl, C6-C9 aryl or substituted C6-C9 aryl, and the substituent in the substituted C6-C9 aryl is C1-C5 alkyl.

[0048] R2 is selected from a C1-C6 alkyl group, a C6-C9 aryl group or a substituted C6-C9 aryl group, and the substituent in the substituted C6-C9 aryl group is a C1-C5 alkyl group.

[0049] Further preferred:

[0050] The R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, 3-methylpropyl, cyclopentyl, cyclohexyl, benzyl, 2-phenylethyl, 3-phenylbutyl, 4-phenylbutyl, 4-methylbenzyl, 4-ethylbenzyl, 4-propylbenzyl, 4-butylbenzyl, 2-methylbenzyl, 2-ethylbenzyl, 2-propylbenzyl, 2-butylbenzyl, 3-methylbenzyl, 3-ethylbenzyl, 3-propylbenzyl or 3-butylbenzyl.

[0051] The R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, 3-methylpropyl, cyclopentyl, cyclohexyl, benzyl, 2-phenylethyl, 3-phenylbutyl, 4-phenylbutyl, 4-methylbenzyl, 4-ethylbenzyl, 4-propylbenzyl, 4-butylbenzyl, 2-methylbenzyl, 2-ethylbenzyl, 2-propylbenzyl, 2-butylbenzyl, 3-methylbenzyl, 3-ethylbenzyl, 3-propylbenzyl or 3-butylbenzyl.

[0052] Or R1 and R2 together form a C4-C9 nitrogen-containing heterocycle or a substituted C4-C9 nitrogen-containing heterocycle, and the substituent in the substituted C4-C9 nitrogen-containing heterocycle is a C1-C6 alkyl group or a C6-C14 aryl group. More specifically, the structure is morpholine, 2-methylmorpholine, 3-methylmorpholine, 2,2-dimethylmorpholine, 2,6-dimethylmorpholine, thiomorpholine, 2-methylthiomorpholine, 3-methylthiomorpholine, 2,2-dimethylthiomorpholine, 2,6-dimethylthiomorpholine, piperidine, 4-methylpiperidine, 4-methoxypiperidine, 4-fluoropiperidine, 4-chloropiperidine, 4-bromopiperidine, 4-trifluoromethylpiperidine, 4-phenylpiperidine, 4-nitropiperidine, 2-methylpiperidine, 3-methylpiperidine, 2,2-dimethylpiperidine, 2,6-dimethylpiperidine, 2,2,6,6-tetramethylpiperidine, 1, 4-dioxa-8-azaspiro[4.5]decane, piperazine, 1-methylpiperazine, 1-phenylpiperazine, 1-formylpiperazine, 1-boc-piperazine, pyrrolidine, 2-methylpyrrolidine, 3-methylpyrrolidine, isoindoline, 4-methylisoindoline, 5-methylisoindoline, 4-methoxyindoline, 4-chloroisoindoline, 1,2,3,4-tetrahydroisoquinoline, 5-methyl-1,2,3,4-tetrahydroisoquinoline, 6-methyl-1,2,3,4-tetrahydroisoquinoline, 7-methyl-1,2,3,4-tetrahydroisoquinoline or 8-methyl-1,2,3,4-tetrahydroisoquinoline.

[0053] Further preferred:

[0054] The compound with the structure of formula (II) is specifically a compound represented by formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6), formula (II-7), formula (II-8) or formula (II-9).

[0055]

[0056] Specifically, the present invention adds a compound having a structure represented by formula (I) and nitromethane into a solvent, and obtains a target product having a structure represented by formula (II) through an electrochemical reaction in the presence of a catalyst and a base.

[0057] in:

[0058] The catalyst is preferably one or more of potassium iodide, sodium iodide, tetramethylammonium iodide, tetraethylammonium iodide, tetrabutylammonium iodide, ammonium iodide, elemental iodine, potassium iodate, 2-iodoacylbenzoic acid, N-iodosuccinimide and iodobenzene acetate, more preferably potassium iodide or tetramethylammonium iodide.

[0059] The base is preferably one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, DABCO, quinoline ring, DBU, DBN, DIPEA, DMAP, triethylamine, trifluoroethanol and hexafluoroisopropanol, more preferably sodium bicarbonate or DABCO.

[0060] The solvent is preferably one or more of toluene, xylene, chloroform, 1,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, water, tetrahydrofuran, 1,2-dichloroethane and dichloromethane, more preferably one or more of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, water, tetrahydrofuran and dichloromethane, more preferably one or more of N,N-dimethylformamide, acetonitrile, water and dichloromethane.

[0061] The electrode material of the reaction is preferably one or more of a carbon electrode, a platinum electrode, a nickel electrode, a zinc electrode, an iron electrode, a copper electrode, and a cobalt electrode, and more preferably one or more of a carbon electrode, a platinum electrode, and a nickel electrode.

[0062] The molar ratio of the secondary amine of formula (I) to the catalyst is 1:(0.01-0.5), more preferably 1:(0.05-0.3); the molar ratio of the secondary amine of formula (I) to the nitromethane is 1:(1-5), preferably 1:(1-3).

[0063] The reaction temperature is 0 to 80°C, preferably 40 to 65°C, and most preferably 45 to 55°C.

[0064] In the present invention, there is no particular limitation on the source of the raw materials, and those skilled in the art can purchase the raw materials or synthesize them by themselves according to known methods for synthesizing raw materials.

[0065] The reaction equation of the synthesis method of the present invention is as follows:

[0066]

[0067] The present invention provides a method for synthesizing nitrosamine compounds. The method comprises reacting a secondary amine having a structure of formula (I) with nitromethane under electrochemical action to obtain a nitrosamine compound having a structure of formula (II). The method realizes, for the first time, a method for obtaining nitrosamine compounds by reacting nitromethane as a nitrosating agent with a secondary amine under electrochemical conditions without adding an additional oxidant through a one-step reaction. The method also has mild reaction conditions and a high reaction yield of the obtained product. The method is green and efficient for synthesizing nitrosamine compounds.

[0068] Based on the reaction results, the possible reaction mechanism is as follows: first, tetramethylammonium iodide in the reaction system is oxidized to elemental iodine at the anode surface, and then to iodine free radicals. Subsequently, at the anode surface, the iodine free radical undergoes a hydrogen atom transfer reaction (HAT reaction) with the substrate nitromethane to form a nitromethane free radical intermediate. This intermediate then couples with the iodine free radical to form an iodine-(nitro)-methane intermediate. However, iodine-(nitro)-methane is unstable in air and rearranges to form the intermediate 2-oxo-1,2-oxacyclopropane-2-ium, which then decomposes to form formaldehyde and a nitroso cation. Finally, a secondary amine undergoes nucleophilic attack on the nitroso cation to form the target product, nitrosamine, while hydrogen ions are reduced at the cathode to release hydrogen.

[0069] The following will be a clear and complete description of the technical solutions of the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of them. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts shall fall within the scope of protection of the present invention.

[0070] All reagents used in the examples were analytically pure reagents purchased directly without any other treatment before use. The solvents or eluents used were purchased from Sinopharm.

[0071] Example 1:

[0072]

[0073] Morpholine (0.3 mmol, 26.1 mg, 26 μL), nitromethane (0.45 mmol, 27.5 mg, 26 μL), tetramethylammonium iodide (0.09 mmol, 18.1 mg), triethylenediamine (0.2 mmol, 22.5 mg), and acetonitrile (6.0 mL) were placed in a 10 mL electrolytic cell tube and stirred at 50°C. After completion of the reaction (TLC monitoring), the resulting residue was spin-dried and eluted with ethyl acetate / petroleum ether to obtain the product, 4-nitrosomorpholine, in a 94% yield and 98% purity.

[0074] The synthesized product was analyzed by nuclear magnetic resonance spectroscopy. Figures 1-2 . Figure 1 The synthetic product provided by Example 1 of the present invention 1 H NMR ( 1 H-NMR) spectrum; Figure 2 The synthetic product provided by Example 1 of the present invention 13 C NMR ( 13 C-NMR) spectrum. Its characterization data is 1 H NMR (500MHz, Acetone-d6) δ4.26(m,2H),3.85(m,2H),3.82–3.76(m,2H),3.65–3.57(m,2H). 13 C NMR (125MHz, Acetone-d6) δ67.0, 65.5, 49.6, 40.0.

[0075] Example 2:

[0076]

[0077] Thiomorpholine (0.3 mmol, 31.0 mg, 30 μL), nitromethane (0.45 mmol, 27.5 mg, 26 μL), tetramethylammonium iodide (0.09 mmol, 18.1 mg), triethylenediamine (0.2 mmol, 22.5 mg), and acetonitrile (6.0 mL) were placed in a 10 mL electrolytic cell tube and stirred at 50°C. After completion of the reaction (TLC monitoring), the resulting residue was dried and eluted with ethyl acetate / petroleum ether to obtain the product, 4-nitrosothiomorpholine, in a 93% yield and 99% purity.

[0078] The synthesized product was analyzed by nuclear magnetic resonance spectroscopy. Figures 3-4 . Figure 3 The synthetic product provided by Example 2 of the present invention 1 H NMR ( 1 H-NMR) spectrum; Figure 4 The synthetic product provided by Example 2 of the present invention 13 C NMR ( 13 C-NMR) spectrum. Its characterization data is 1 HNMR(500MHz,Chloroform-d)δ4.56–4.47(m,2H),4.13–4.00(m,2H),2.95–2.82(m,2H),2.63–2.55(m,2H). 13 C NMR(125MHz,Chloroform-d)δ52.4,41.3,28.9,27.3.

[0079] Example 3:

[0080]

[0081] A 10 mL electrolytic cell test tube was charged with 1,4-dioxa-8-azaspiro[4.5]decane (0.3 mmol, 43.0 mg), nitromethane (0.45 mmol, 27.5 mg, 26 μL), tetramethylammonium iodide (0.09 mmol, 18.1 mg), triethylenediamine (0.2 mmol, 22.5 mg), and acetonitrile (6.0 mL). The reaction was stirred at 50°C. After completion of the reaction (TLC monitoring), the resulting residue was spin-dried and eluted with ethyl acetate / petroleum ether to obtain the product, 8-nitroso-1,4-dioxa-8-aza[4.5]decane, in a 97% yield and 99% purity.

[0082] The synthesized product was analyzed by nuclear magnetic resonance spectroscopy. Figures 5-6 . Figure 5 The synthetic product provided by Example 3 of the present invention 1 H NMR ( 1 H-NMR) spectrum; Figure 6 The synthetic product provided by Example 3 of the present invention 13 C NMR ( 13 C-NMR) spectrum. Its characterization data is 1 HNMR (500MHz, Acetone-d6) δ4.33–4.27 (m, 1H), 4.01 (t, J = 1.4Hz, 2H), 3.84–3. 78(m,1H),1.91(ddd,J=7.1,5.4,1.2Hz,1H),1.63(ddd,J=7.4,5.6,1.2Hz,1H). 13 C NMR (125MHz, Acetone-d6) δ106.6,64.4,47.2,36.0,35.0,33.4.

[0083] Example 4:

[0084]

[0085] In a 10mL electrolytic cell tube, 1-formylpiperazine (0.3mmol, 34.2mg, 31μL), nitromethane (0.45mmol, 27.5mg, 26μL), tetramethylammonium iodide (0.09mmol, 18.1mg), triethylenediamine (0.2mmol, 22.5mg), and acetonitrile (6.0mL) were placed and stirred at 50°C. After completion of the reaction (TLC monitoring), the resulting residue was spin-dried and eluted with ethyl acetate / petroleum ether to obtain the product, 4-nitrosopiperazine-1-carboxaldehyde, in an 84% yield and 97% purity.

[0086] The synthesized product was analyzed by nuclear magnetic resonance spectroscopy. Figures 7-8 . Figure 7 The synthetic product provided by Example 4 of the present invention 1 H NMR ( 1 H-NMR) spectrum; Figure 8 The synthetic product provided by Example 4 of the present invention 13 C NMR ( 13 C-NMR) spectrum.

[0087] The product was measured and its characterization data were 1 H NMR(500MHz,Chloroform-d)δ8.10(d,J=18.5Hz,1H),4.30–4.27(m,1H),4.24(dd,J=6.3,4.6Hz,1H),3.82(dd,J=6.4,4. 7Hz,1H),3.76(ddd,J=15.9,6.2,4.7Hz,2H),3.64–3.57(m,1H),3.49(dd,J=6.5,4.7Hz,1H),3.36(dd,J=6.4,4.6Hz,1H). 13 C NMR (125MHz, Chloroform-d) δ161.0,160.9,50.0,48.8,45.7,44.0,40.2,39.9,38.8,38.6.

[0088] Example 5:

[0089]

[0090] Pyrrolidine (0.3 mmol, 21.3 mg, 25 μL), nitromethane (0.45 mmol, 27.5 mg, 26 μL), tetramethylammonium iodide (0.09 mmol, 18.1 mg), triethylenediamine (0.2 mmol, 22.5 mg), and acetonitrile (6.0 mL) were placed in a 10 mL electrolytic cell tube and stirred at 50°C. After completion of the reaction (TLC monitoring), the resulting residue was spin-dried and eluted with ethyl acetate / petroleum ether to obtain the product, 1-nitrosopyrrolidine, in an 82% yield and 98% purity.

[0091] The synthesized product was analyzed by nuclear magnetic resonance spectroscopy. Figures 9-10 . Figure 9 The synthetic product provided by Example 5 of the present invention 1 H NMR ( 1 H-NMR) spectrum; Figure 10 The synthetic product provided by Example 5 of the present invention 13 C NMR ( 13 C-NMR) spectrum. Its characterization data is 1 HNMR(500MHz,Chloroform-d)δ4.27(t,J=6.7Hz,2H),3.59(t,J=7.1Hz,2H),2.12–1.96(m,4H). 13 C NMR (125MHz, Chloroform-d) δ48.8, 44.2, 23.0, 21.6.

[0092] Example 6:

[0093]

[0094] A 10mL electrolytic cell test tube was charged with N,N-dicyclohexylamine (0.3mmol, 54.4mg, 60μL), nitromethane (0.45mmol, 27.5mg, 26μL), tetramethylammonium iodide (0.09mmol, 18.1mg), triethylenediamine (0.2mmol, 22.5mg), and acetonitrile (6.0mL). The reaction was stirred at 50°C. After completion of the reaction (TLC monitoring), the resulting residue was spin-dried and eluted with ethyl acetate / petroleum ether to obtain the product, N,N-dicyclohexylnitrosamide, in a 73% yield and 99% purity.

[0095] The synthesized product was analyzed by nuclear magnetic resonance spectroscopy. Figures 11-12 . Figure 11 The synthetic product provided by Example 6 of the present invention 1 H NMR ( 1H-NMR) spectrum; Figure 12 The synthetic product provided by Example 6 of the present invention 13 C NMR ( 13 C-NMR) spectrum. Its characterization data is 1 H NMR(500MHz,Chloroform-d)δ4.87(tt,J=12.0,3.8Hz,1H),3.72(tt,J=11.3,4.4Hz,1H),1.99–1.85(m,6H),1 .80(d,J=13.1Hz,2H),1.75–1.65(m,2H),1.59(dd,J=12.0,3.6Hz,2H),1.39(m,6H),1.26(m,1H),1.15(m,1H). 13 C NMR (125MHz, Chloroform-d) δ58.6,52.2,34.4,29.4,26.1,25.5,25.4,25.2.

[0096] Example 7:

[0097]

[0098] A 10mL electrolytic cell test tube was charged with 1,2,3,4-tetrahydroisoquinoline (0.3mmol, 40.0mg, 38μL), nitromethane (0.45mmol, 27.5mg, 26μL), tetramethylammonium iodide (0.09mmol, 18.1mg), triethylenediamine (0.2mmol, 22.5mg), and acetonitrile (6.0mL). The reaction was stirred at 50°C. After completion of the reaction (TLC monitoring), the resulting residue was spin-dried and eluted with ethyl acetate / petroleum ether to obtain the product, 2-nitroso-1,2,3,4-tetrahydroisoquinoline, in an 84% yield and 98% purity.

[0099] The synthesized product was analyzed by nuclear magnetic resonance spectroscopy. Figures 13-14 . Figure 13 The synthetic product provided by Example 7 of the present invention 1 H NMR ( 1 H-NMR) spectrum; Figure 14 The synthetic product provided by Example 7 of the present invention 13 C NMR ( 13 C-NMR) spectrum. Its characterization data is 1H NMR(500MHz,Chloroform-d)δ7.29–7.14(m,4H),4.83(5.39)(s,2H),4.54(3.88)(t,J=5.9Hz,2H),3.10(2.96)(t,J=5.9Hz,2H). 13 C NMR(125MHz,Chloroform-d)δ135.0(133.9),132.4,130.0,128.7,128.1,128.0,127.3,127.3,127.2,126.2,51.3,47.8,44.5,40.8,29.8,27.4.

[0100] Example 8:

[0101]

[0102] A 10 mL electrolytic cell test tube was charged with N-methylphenylethylamine (0.3 mmol, 40.6 mg, 44 μL), nitromethane (0.45 mmol, 27.5 mg, 26 μL), tetramethylammonium iodide (0.09 mmol, 18.1 mg), triethylenediamine (0.2 mmol, 22.5 mg), and acetonitrile (6.0 mL). The reaction was stirred at 50°C. After completion of the reaction (TLC monitoring), the resulting residue was spin-dried and eluted with ethyl acetate / petroleum ether to obtain the product, N-methyl-N-phenylethylnitrosamide, in a 72% yield and 95% purity.

[0103] The synthesized product was analyzed by nuclear magnetic resonance spectroscopy. Figures 15-16 . Figure 15 The synthetic product provided by Example 8 of the present invention 1 H NMR ( 1 H-NMR) spectrum; Figure 16 The synthetic product provided by Example 8 of the present invention 13 C NMR ( 13 C-NMR) spectrum. Its characterization data is 1 H NMR(500MHz,Chloroform-d)δ7.39–7.10(m,5H),4.37(3.78)(t,2H),3.04(2.80)(t,2H),2.98(3.56)(s,3H). 13 C NMR(125MHz,Chloroform-d)δ138.0,137.3,128.8,128.7,128.7,127.0,126.8,55.1,47.1,39.8,35.1,32.0,31.8

[0104] Example 9:

[0105]

[0106] A 10 mL electrolytic cell test tube was charged with 8-chloro-11-(piperidin-4-ylene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-β]pyridine (0.3 mmol, 93.2 mg), nitromethane (0.45 mmol, 27.5 mg, 26 μL), tetramethylammonium iodide (0.09 mmol, 18.1 mg), triethylenediamine (0.2 mmol, 22.5 mg), and acetonitrile (6.0 mL). The reaction was stirred at 50°C. After completion of the reaction (TLC monitoring), the resulting residue was dried and eluted with ethyl acetate / petroleum ether to afford the product, 8-chloro-11-(1-nitrosopiperidin-4-ylene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-β]pyridine, in a yield of 78% and a purity of 97%.

[0107] The synthesized product was analyzed by nuclear magnetic resonance spectroscopy. Figures 17-18 , Figure 17 The synthetic product provided by Comparative Example 1 of the present invention 1 H NMR ( 1 H-NMR) spectrum; Figure 18 The synthetic product provided by Comparative Example 1 of the present invention 13 C NMR ( 13 C-NMR) spectrum. Its characterization data is 1 HNMR(500MHz,Chloroform-d)δ8.41(ddd,J=9.8,4.9,1.7Hz,1H),7.47(td,J=7.6,1.7Hz,1H),7.22–7.07(m,4H), 4.53–4.38(m,1H),4.21–4.02(m,2H),3.59–3.47(m,1H),3.44–3.27(m,2H),2.93–2.76(m,2H),2.71–2.33(m,4H). 13C NMR(125MHz,Chloroform-d)δ156.4,156.1,146.7(d,J=3.5Hz),139.6,138.0 (d,J=6.8Hz),137.5,137.3,136.2,136.1,135.1,135.0,133.4(d,J=2.8Hz), 133.3,130.1(d,J=12.8Hz),129.1(d,J=5.3Hz),126.4(d,J=4.6Hz),122.6,4 9.9(d,J=18.6Hz),40.3(d,J=11.7Hz),31.6–31.4(m),31.0,30.7,28.8,28.6.

[0108] HRMS(ESI)m / z calcd for C 19 H 18 N3OCl[M+Na] + 340.1211, found 340.1216.

[0109] Example 10:

[0110]

[0111] Morpholine (0.3 mmol, 26.1 mg, 26 μL), nitromethane (0.45 mmol, 27.5 mg, 26 μL), potassium iodide (0.09 mmol, 14.9 mg), triethylenediamine (0.2 mmol, 22.5 mg), and acetonitrile (6.0 mL) were placed in a 10 mL electrolytic cell tube and stirred at 50°C. After completion of the reaction (TLC monitoring), the resulting residue was dried and eluted with ethyl acetate / petroleum ether to obtain the product, 4-nitrosomorpholine, in an 87% yield and 97% purity.

[0112] The characterization data is 1 H NMR (500MHz, Acetone-d6) δ4.26(m,2H),3.85(m,2H),3.82–3.76(m,2H),3.65–3.57(m,2H). 13 C NMR (125MHz, Acetone-d6) δ67.0, 65.5, 49.6, 40.0.

[0113] Example 11:

[0114]

[0115] Morpholine (0.3 mmol, 26.1 mg, 26 μL), nitromethane (0.45 mmol, 27.5 mg, 26 μL), tetrabutylammonium iodide (0.09 mmol, 33.2 mg), triethylenediamine (0.2 mmol, 22.5 mg), and acetonitrile (6.0 mL) were placed in a 10 mL electrolytic cell tube and stirred at 50°C. After completion of the reaction (TLC monitoring), the resulting residue was dried and eluted with ethyl acetate / petroleum ether to obtain the product, 4-nitrosomorpholine, in an 83% yield and 98% purity.

[0116] The characterization data is 1 H NMR (500MHz, Acetone-d6) δ4.26(m,2H),3.85(m,2H),3.82–3.76(m,2H),3.65–3.57(m,2H). 13 C NMR (125MHz, Acetone-d6) δ67.0, 65.5, 49.6, 40.0.

[0117] Example 12:

[0118]

[0119] Morpholine (0.3 mmol, 26.1 mg, 26 μL), nitromethane (0.45 mmol, 27.5 mg, 26 μL), sodium iodide (0.09 mmol, 13.5 mg), triethylenediamine (0.2 mmol, 22.5 mg), and acetonitrile (6.0 mL) were placed in a 10 mL electrolytic cell tube and stirred at 50°C. After completion of the reaction (TLC monitoring), the resulting residue was spin-dried and eluted with ethyl acetate / petroleum ether to obtain the product, 4-nitrosomorpholine, in an 80% yield and 95% purity.

[0120] The characterization data is 1 H NMR (500MHz, Acetone-d6) δ4.26(m,2H),3.85(m,2H),3.82–3.76(m,2H),3.65–3.57(m,2H). 13 C NMR (125MHz, Acetone-d6) δ67.0, 65.5, 49.6, 40.0.

[0121] Example 13:

[0122]

[0123] Morpholine (0.3 mmol, 26.1 mg, 26 μL), nitromethane (0.45 mmol, 27.5 mg, 26 μL), tetramethylammonium iodide (0.09 mmol, 18.1 mg), sodium carbonate (0.2 mmol, 21.2 mg), and acetonitrile (6.0 mL) were placed in a 10 mL electrolytic cell tube and stirred at 50°C. After completion of the reaction (TLC monitoring), the resulting residue was spin-dried and eluted with ethyl acetate / petroleum ether to obtain the product, 4-nitrosomorpholine, with a yield of 90% and a purity of 97%.

[0124] The characterization data is 1 H NMR (500MHz, Acetone-d6) δ4.26(m,2H),3.85(m,2H),3.82–3.76(m,2H),3.65–3.57(m,2H). 13 C NMR (125MHz, Acetone-d6) δ67.0, 65.5, 49.6, 40.0.

[0125] Example 14:

[0126]

[0127] Morpholine (0.3 mmol, 26.1 mg, 26 μL), nitromethane (0.45 mmol, 27.5 mg, 26 μL), tetramethylammonium iodide (0.09 mmol, 18.1 mg), potassium carbonate (0.2 mmol, 27.6 mg), and acetonitrile (6.0 mL) were placed in a 10 mL electrolytic cell tube and stirred at 50°C. After completion of the reaction (TLC monitoring), the resulting residue was spin-dried and eluted with ethyl acetate / petroleum ether to obtain the product, 4-nitrosomorpholine, in an 86% yield and 98% purity.

[0128] The characterization data is 1 H NMR (500MHz, Acetone-d6) δ4.26(m,2H),3.85(m,2H),3.82–3.76(m,2H),3.65–3.57(m,2H). 13 C NMR (125MHz, Acetone-d6) δ67.0, 65.5, 49.6, 40.0.

[0129] Example 15:

[0130]

[0131] Morpholine (0.3 mmol, 26.1 mg, 26 μL), nitromethane (0.45 mmol, 27.5 mg, 26 μL), tetramethylammonium iodide (0.09 mmol, 18.1 mg), 1,8-diazabicyclo(5,4,0)-7-undecene (0.2 mmol, 30.4 mg), and acetonitrile (6.0 mL) were placed in a 10 mL electrolytic cell tube and stirred at 50°C. After completion of the reaction (TLC monitoring), the resulting residue was dried and eluted with ethyl acetate / petroleum ether to obtain the product, 4-nitrosomorpholine, in an 84% yield and 96% purity.

[0132] The characterization data is 1 H NMR (500MHz, Acetone-d6) δ4.26(m,2H),3.85(m,2H),3.82–3.76(m,2H),3.65–3.57(m,2H). 13 C NMR (125MHz, Acetone-d6) δ67.0, 65.5, 49.6, 40.0.

[0133] Example 16:

[0134]

[0135] Morpholine (0.3 mmol, 26.1 mg, 26 μL), nitromethane (0.45 mmol, 27.5 mg, 26 μL), tetramethylammonium iodide (0.09 mmol, 18.1 mg), trifluoroethanol (0.2 mmol, 20.6 mg), and acetonitrile (6.0 mL) were placed in a 10 mL electrolytic cell tube and stirred at 50°C. After completion of the reaction (TLC monitoring), the resulting residue was spin-dried and eluted with ethyl acetate / petroleum ether to obtain the product, 4-nitrosomorpholine, in an 88% yield and 97% purity.

[0136] The characterization data is 1 H NMR (500MHz, Acetone-d6) δ4.26(m,2H),3.85(m,2H),3.82–3.76(m,2H),3.65–3.57(m,2H). 13 C NMR (125MHz, Acetone-d6) δ67.0, 65.5, 49.6, 40.0.

[0137] Example 17:

[0138]

[0139] Morpholine (0.3 mmol, 26.1 mg, 26 μL), nitromethane (0.45 mmol, 27.5 mg, 26 μL), tetramethylammonium iodide (0.09 mmol, 18.1 mg), potassium hydroxide (0.2 mmol, 11.2 mg), and acetonitrile (6.0 mL) were placed in a 10 mL electrolytic cell tube and stirred at 50°C. After completion of the reaction (TLC monitoring), the resulting residue was spin-dried and eluted with ethyl acetate / petroleum ether to obtain the product, 4-nitrosomorpholine, in a 78% yield and 98% purity.

[0140] The characterization data is 1 H NMR (500MHz, Acetone-d6) δ4.26(m,2H),3.85(m,2H),3.82–3.76(m,2H),3.65–3.57(m,2H). 13 C NMR (125MHz, Acetone-d6) δ67.0, 65.5, 49.6, 40.0.

[0141] Example 18:

[0142]

[0143] Morpholine (0.3 mmol, 26.1 mg, 26 μL), nitromethane (0.45 mmol, 27.5 mg, 26 μL), tetramethylammonium iodide (0.09 mmol, 18.1 mg), triethylenediamine (0.2 mmol, 22.5 mg), and N,N-dimethylformamide (6.0 mL) were placed in a 10 mL electrolytic cell tube and stirred at 50°C. After completion of the reaction (TLC monitoring), the resulting residue was spin-dried and eluted with ethyl acetate / petroleum ether to obtain the product, 4-nitrosomorpholine, in a 78% yield and 97% purity.

[0144] The characterization data is 1 H NMR (500MHz, Acetone-d6) δ4.26(m,2H),3.85(m,2H),3.82–3.76(m,2H),3.65–3.57(m,2H). 13 C NMR (125MHz, Acetone-d6) δ67.0, 65.5, 49.6, 40.0.

[0145] Example 19:

[0146]

[0147] Morpholine (0.3 mmol, 26.1 mg, 26 μL), nitromethane (0.45 mmol, 27.5 mg, 26 μL), tetramethylammonium iodide (0.09 mmol, 18.1 mg), triethylenediamine (0.2 mmol, 22.5 mg), and dimethyl sulfoxide (6.0 mL) were placed in a 10 mL electrolytic cell tube and stirred at 50°C. After completion of the reaction (TLC monitoring), the resulting residue was spin-dried and eluted with ethyl acetate / petroleum ether to obtain the product, 4-nitrosomorpholine, in an 86% yield and 97% purity.

[0148] Example 20:

[0149]

[0150] Morpholine (0.3 mmol, 26.1 mg, 26 μL), nitromethane (0.45 mmol, 27.5 mg, 26 μL), tetramethylammonium iodide (0.09 mmol, 18.1 mg), triethylenediamine (0.2 mmol, 22.5 mg), and tetrahydrofuran (6.0 mL) were placed in a 10 mL electrolytic cell tube and stirred at 50°C. After completion of the reaction (TLC monitoring), the resulting residue was spin-dried and eluted with ethyl acetate / petroleum ether to obtain the product, 4-nitrosomorpholine, in a 70% yield and 95% purity.

[0151] The characterization data is 1 H NMR (500MHz, Acetone-d6) δ4.26(m,2H),3.85(m,2H),3.82–3.76(m,2H),3.65–3.57(m,2H). 13 C NMR (125MHz, Acetone-d6) δ67.0, 65.5, 49.6, 40.0.

[0152] The above embodiments are only intended to help understand the method and core concept of the present invention. It should be noted that, without departing from the principles of the present invention, a number of improvements and modifications may be made to the present invention by those skilled in the art, and such improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A method for synthesizing a nitrosamine organic compound, characterized in that: The compound of formula (I) and nitromethane are added to a solvent, and an electrochemical reaction is performed in the presence of a catalyst and a base to obtain a target product of formula (II). ； in: R1 is selected from a C1-C6 alkyl group, a C6-C9 aryl group, or a substituted C6-C9 aryl group, wherein the substituent in the substituted C6-C9 aryl group is a C1-C5 alkyl group; R2 is selected from a C1-C6 alkyl group, a C6-C9 aryl group, or a substituted C6-C9 aryl group, wherein the substituent in the substituted C6-C9 aryl group is a C1-C5 alkyl group; or R1 and R2 together form a C4-C9 nitrogen-containing heterocycle or a substituted C4-C9 nitrogen-containing heterocycle, and the substituent in the substituted C4-C9 nitrogen-containing heterocycle is a C1-C6 alkyl group or a C6-C14 aryl group; The catalyst is selected from one or more of potassium iodide, sodium iodide, tetramethylammonium iodide, tetraethylammonium iodide, tetrabutylammonium iodide, ammonium iodide, elemental iodine, potassium iodate, 2-iodoacylbenzoic acid, N-iodosuccinimide, and iodobenzene acetate; The base is selected from one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, DABCO, quinoline ring, DBU, DBN, DIPEA, DMAP, triethylamine, trifluoroethanol and hexafluoroisopropanol; The solvent is selected from one or more of toluene, xylene, chloroform, 1,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, acetone, tetrahydrofuran, 1,2-dichloroethane, and dichloromethane.

2. The synthesis method according to claim 1, wherein: R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, 3-methylpropyl, cyclopentyl, cyclohexyl, benzyl, 2-phenylethyl, 3-phenylbutyl, 4-phenylbutyl, 4-methylbenzyl, 4-ethylbenzyl, 4-propylbenzyl, 4-butylbenzyl, 2-methylbenzyl, 2-ethylbenzyl, 2-propylbenzyl, 2-butylbenzyl, 3-methylbenzyl, 3-ethylbenzyl, 3-propylbenzyl or 3-butylbenzyl; The R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, 3-methylpropyl, cyclopentyl, cyclohexyl, benzyl, 2-phenylethyl, 3-phenylbutyl, 4-phenylbutyl, 4-methylbenzyl, 4-ethylbenzyl, 4-propylbenzyl, 4-butylbenzyl, 2-methylbenzyl, 2-ethylbenzyl, 2-propylbenzyl, 2-butylbenzyl, 3-methylbenzyl, 3-ethylbenzyl, 3-propylbenzyl or 3-butylbenzyl.

3. The synthesis method according to claim 1, wherein: R1 and R2 together form a C4-C6 nitrogen-containing heterocycle or a substituted C4-C6 nitrogen-containing heterocycle, wherein the C4-C9 nitrogen-containing heterocycle is pyrrole, piperidine, piperazine, morpholine, thiomorpholine, isoindoline or tetrahydroisoquinoline; and the substituent in the substituted C4-C9 nitrogen-containing heterocycle is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen, a nitro group or a C6-C14 aryl group.

4. The synthesis method according to claim 1, wherein: The compound of formula (II) is specifically a compound represented by formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6), formula (II-7), formula (II-8) or formula (II-9); 。 5. The synthesis method according to claim 1, wherein: The molar ratio of the compound represented by formula (I) to nitromethane is 1:1-5.

6. The synthesis method according to claim 1, wherein: During the electrochemical reaction, the electrode material is selected from one or more of a carbon electrode, a platinum electrode, a nickel electrode, a zinc electrode, an iron electrode, a copper electrode, and a cobalt electrode.

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