Synthetic method of nitrosamine organic compound

Abstract

The invention discloses a synthetic method of a nitrosamine organic compound, which comprises the following step: reacting a compound with a structure shown in a formula (I) with nitromethane under the electrochemical action to obtain the nitrosamine organic compound with a structure shown in a formula (II). The nitrosation of the secondary amine is realized through one-step reaction, the reaction condition is mild, the reaction yield of the obtained product is high, and the product has a reusable medicinal value, so that the synthesis method has a very good application prospect. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular 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, formostergine, streptozotocin, etc. The derivatives of some drugs after nitrosation also have important medicinal value, such as Form Desloratadine, which is an antihistamine used to relieve systemic and local symptoms of chronic idiopathic urticaria and perennial allergic rhinitis. In addition to important biomedical applications, NOCs are also important intermediates in organic synthesis, which help to prepare hydrazines and nitro compounds. Therefore, people have paid great attention to the synthesis of NOCs, and an increasing number of methods have been developed.

[0003] The traditional synthesis method of NOCs is to N-nitrosate secondary amines. The most commonly used nitrosation reagents are: NaNO2, tert-butyl nitrite (TBN), Fremi salt (dipotassium nitrosodisulfonate), nitrite peroxide and bis(triphenylphosphinoylidene)ammonium nitrite. However, these methods require the use of large amounts of metals or chemical oxidants, and most of the reagents are flammable and explosive, and the substrates are limited to aromatic secondary amines. Therefore, it is necessary to develop more environmentally friendly and efficient methods to synthesize alkyl nitrosamines.

[0004] Organic electrochemistry is currently considered to be an environmentally friendly, sustainable and green synthesis method that avoids the use of oxidants by transferring electrons between electrodes and substrates or catalysts. At present, some methods for synthesizing NOCs under electrochemistry have been reported, but the nitrosating agents used in these methods are mostly flammable and explosive, and require metal catalysis or reactions in an inert atmosphere. The conditions are relatively harsh, and the yields are mostly medium to low.

[0005] We have long been focusing on halogen-mediated electrochemical organic synthesis. In addition, we have studied the reactivity of nitromethane under electrocatalysis and achieved some remarkable results. On this basis, we used nitromethane as a nitroso reagent and secondary amines as reactants to design an electrochemical method to synthesize NOCs under catalyst-free conditions. Summary of the invention

[0006] In view of this, the present invention provides a method for synthesizing nitrosamine organic compounds. The method can use nitromethane to nitrosate secondary amines 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 the compound of the structure shown in formula (I) with nitromethane under electrochemical action to obtain the nitrosamine organic compound of the structure shown in 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] 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; 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 further:

[0017] The compound of the structure of formula (II) is specifically a compound shown 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 the 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 a method for obtaining nitrosamine compounds under electrochemical conditions by using nitromethane as a nitroso reagent to react with a secondary amine 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] Fig. 9 The synthetic product provided by Example 5 of the present invention 1 H NMR ( 1 H-NMR) spectrum.

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

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

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

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

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

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

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

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

[0043] Fig.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 react 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 C1-C6 alkyl, C6-C9 aryl or substituted C6-C9 aryl, and the substituent in the substituted C6-C9 aryl is C1-C5 alkyl.

[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 of the structure of formula (II) is specifically a compound shown 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 with a structure shown in formula (I) and nitromethane into a solvent, and obtains a target product with a structure shown in 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, the source of the raw materials is not particularly limited, and those skilled in the art can purchase them 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 the steps of 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 nitroso reagent 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 in synthesizing nitrosamine compounds.

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

[0069] The following will be described clearly and completely in conjunction with the technical solutions of the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

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

[0071] Embodiment 1:

[0072]

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

[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 are 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] Embodiment 2:

[0076]

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

[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 are 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] Embodiment 3:

[0080]

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

[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 are 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] Embodiment 4:

[0084]

[0085] In a 10mL electrolytic cell test 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 the reaction was stirred at 50°C. After the reaction was completed (TLC tracking detection), the residue was spin-dried and chromatographically eluented with ethyl acetate / petroleum ether system to obtain the product 4-nitrosopiperazine-1-carboxaldehyde, with a yield of 84% and a purity of 97%.

[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] Embodiment 5:

[0089]

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

[0091] The synthesized product was analyzed by nuclear magnetic resonance spectroscopy. Figures 9-10 . Fig. 9 The synthetic product provided by Example 5 of the present invention 1 H NMR ( 1 H-NMR) spectrum; Fig.10 The synthetic product provided by Example 5 of the present invention 13 C NMR ( 13 C-NMR) spectrum. Its characterization data are 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] Embodiment 6:

[0093]

[0094] In a 10mL electrolytic cell test tube, 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) were placed, and the reaction was stirred at 50°C. After the reaction was completed (TLC tracking detection), the residue was spin-dried and chromatographically elute with ethyl acetate / petroleum ether system to obtain the product N, N-dicyclohexylnitrosamide, with a yield of 73% and a purity of 99%.

[0095] The synthesized product was analyzed by nuclear magnetic resonance spectroscopy. Figures 11-12 . Fig.11 The synthetic product provided by Example 6 of the present invention 1 H NMR ( 1H-NMR) spectrum; Fig.12 The synthetic product provided by Example 6 of the present invention 13 C NMR ( 13 C-NMR) spectrum. Its characterization data are 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] Embodiment 7:

[0097]

[0098] 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) were placed in a 10mL electrolytic cell test tube and stirred at 50°C. After the reaction was completed (TLC tracking detection), the residue was spin-dried and chromatographically elute with ethyl acetate / petroleum ether system to obtain the product 2-nitroso-1,2,3,4-tetrahydroisoquinoline with a yield of 84% and a purity of 98%.

[0099] The synthesized product was analyzed by nuclear magnetic resonance spectroscopy. Figures 13-14 . Fig.13 The synthetic product provided by Example 7 of the present invention 1 H NMR ( 1 H-NMR) spectrum; Fig.14 The synthetic product provided by Example 7 of the present invention 13 C NMR ( 13 C-NMR) spectrum. Its characterization data are 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] Embodiment 8:

[0101]

[0102] In a 10mL electrolytic cell test tube, N-methylphenylethylamine (0.3mmol, 40.6mg, 44μL), nitromethane (0.45mmol, 27.5mg, 26μL), tetramethylammonium iodide (0.09mmol, 18.1mg), triethylenediamine (0.2mmol, 22.5mg) and acetonitrile (6.0mL) were placed, and the reaction was stirred at 50°C. After the reaction was completed (TLC tracking detection), the residue was spin-dried and chromatographically eluented with ethyl acetate / petroleum ether system to obtain the product N-methyl-N-phenylethylnitrosamide, with a yield of 72% and a purity of 95%.

[0103] The synthesized product was analyzed by nuclear magnetic resonance spectroscopy. Figures 15-16 . Fig.15 The synthetic product provided by Example 8 of the present invention 1 H NMR ( 1 H-NMR) spectrum; Fig.16 The synthetic product provided by Example 8 of the present invention 13 C NMR ( 13 C-NMR) spectrum. Its characterization data are 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] Embodiment 9:

[0105]

[0106] 8-chloro-11-(piperidin-4-diene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-β]pyridine (0.3mmol, 93.2mg), nitromethane (0.45mmol, 27.5mg, 26μL), tetramethylammonium iodide (0.09mmol, 18.1mg), triethylenediamine (0.2mmol, 22.5mg) and acetonitrile (6.0mL) were placed in a 10mL electrolytic cell test tube and stirred at 50°C. After the reaction was completed (TLC tracking detection), the residue was spin-dried and chromatographically elute with ethyl acetate / petroleum ether system as eluent to obtain the product 8-chloro-11-(1-nitrosopiperidin-4-diene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-β]pyridine with a yield of 78% and a purity of 97%.

[0107] The synthesized product was analyzed by nuclear magnetic resonance spectroscopy. Figures 17-18 , Fig.17 The synthetic product provided by Comparative Example 1 of the present invention 1 H NMR ( 1 H-NMR) spectrum; Fig.18 The synthetic product provided by Comparative Example 1 of the present invention 13 C NMR ( 13 C-NMR) spectrum. Its characterization data are 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] Embodiment 10:

[0110]

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

[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] Embodiment 11:

[0114]

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

[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] Embodiment 12:

[0118]

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

[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] Embodiment 13:

[0122]

[0123] Morpholine (0.3mmol, 26.1mg, 26μL), nitromethane (0.45mmol, 27.5mg, 26μL), tetramethylammonium iodide (0.09mmol, 18.1mg), sodium carbonate (0.2mmol, 21.2mg) and acetonitrile (6.0mL) were placed in a 10mL electrolytic cell test tube and stirred at 50°C. After the reaction was completed (TLC tracking detection), the residue was spin-dried and chromatographically elute with ethyl acetate / petroleum ether system 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] Embodiment 14:

[0126]

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

[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] Embodiment 15:

[0130]

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

[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] Embodiment 16:

[0134]

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

[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] Embodiment 17:

[0138]

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

[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] Embodiment 18:

[0142]

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

[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] Embodiment 19:

[0146]

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

[0148] Embodiment 20:

[0149]

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

[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 used to help understand the method and core idea of ​​the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made to the present invention without departing from the principles of the present invention, and these 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 the structure represented by formula (I) and nitromethane react under electrochemical action to obtain a nitrosamine organic compound of the structure represented by formula (II); in: 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; 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.

2. The synthesis method according to claim 1, characterized in that: 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; 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, characterized in that: 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; 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.

4. The synthesis method according to claim 1, characterized in that: The compound of 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); 5. The synthesis method according to claim 1, 2, 3 or 4, characterized in that: The compound with the structure shown in formula (I) and nitromethane are added into a solvent, and the target product with the structure shown in formula (II) is obtained by electrochemical reaction in the presence of a catalyst and a base.

6. The synthesis method according to claim 5, characterized in that: The molar ratio of the compound with the structure shown in formula (I) to nitromethane is 1:1-5.

7. The synthesis method according to claim 5, characterized in that: 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.

8. The synthesis method according to claim 5, characterized in that: 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.

9. The synthesis method according to claim 5, characterized in that: 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.

10. The synthesis method according to claim 5, characterized in that: 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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