Flow Synthesis

Abstract

A two-step electrochemical flow synthesis of nitroamines, including an electrochemical continuous flow nitrosylation method for the synthesis of N-nitrosamines, comprising: i) reacting a nitroamine represented by formula (I), wherein R 1 and R 2 are independently selected from H, alkyl, aryl, phenyl, cycloalkyl, heterocycle, and aromatic heterocycle, or are taken together to form a cycloalkyl, heterocycle, or aromatic heterocycle.) in a first solvent to form an input flow reagent A; ii) preparing an input flow reagent B which is an aqueous nitrite solution; iii) introducing input flow reagents A and B into a continuous electrochemical flow reactor equipped with electrodes for electrolysis at a predetermined flow rate to produce a reaction solution containing an N-nitrosamine of formula (II); and a subsequent step of continuous flow electrochemically oxidizing the compound of formula II to form a compound of formula III. [Formula 1] JPEG2026504109000019.jpg17170

Description

[Technical Field]

[0001] The present invention relates to chemical compound synthesis, and in particular to electrochemical flow synthesis nitrosylation for the synthesis of N-nitrosamines and their subsequent oxidation to N-nitramines. [Background technology]

[0002] The formation of explosive compounds typically involves the use of batch synthesis to form large quantities of explosive materials, which poses a significant explosion hazard. Summary of the Invention

[0003] Before describing the present invention in further detail, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the scope of the present invention will be limited only by the claims and that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0004] A first aspect of the present invention provides an electrochemical continuous flow nitrosylation method for the synthesis of N-nitrosamines, the method comprising: i) Formula (I)

[0005] [ka]

[0006] (In the formula, R 1 and R 2 are independently selected from H, alkyl, aryl, phenyl, cycloalkyl, heterocyclic rings, and aromatic heterocyclic rings, or are taken together to form a heterocyclic ring or an aromatic heterocyclic ring; ii) preparing an input flow reagent B, which is an aqueous nitrite solution; iii) The input flow reagents A and B are introduced at a predetermined flow rate into a continuous electrochemical flow reactor equipped with electrodes for electrolysis, and a compound of formula II is obtained.

[0007] [ka]

[0008] producing a reaction solution containing an N-nitrosamine represented by the formula: Includes:

[0009] The nitrite may be any suitable nitrite, for example, tetrabutylammonium nitrite, a Group I metal nitrite, a Group II metal nitrite, preferably a Group I metal nitrite such as KNO2 or NaNO2, more preferably NaNO2.

[0010] The conditions are an acid-free, oxidant-free, electrolyte-free continuous flow electrochemical strategy for the synthesis of N-nitrosamines from their corresponding primary or secondary amines.

[0011] The first solvent may be a suitable solvent in which the amine of formula I is soluble, preferably a polar organic solvent, more preferably the solvent may be MeCN or MeOH.

[0012] The anode may be selected from any suitable anode, such as, for example, boron doped diamond (BDD) or graphite.

[0013] The cathode may be an inert metal, preferably platinum.

[0014] The reaction may be followed by a post-treatment in step iv), for example, by addition of HCl (aq) The reaction solution may be washed with a dilute acid such as, for example, 1,2-dimethyl-2,4-trimethyl-1,4-trimethyl ...

[0015] Input flow reagent A, the amine compound represented by formula (I), may be a 0.01M to 5M solution in the first solvent.

[0016] Input flow reagent B, the aqueous nitrite solution, may be a 0.01M to 5M solution.

[0017] Preferably, the concentration of the aqueous nitrite solution may be at least twice the concentration of the amine compound represented by formula (I).

[0018] Preferably, R of formula II 1 and R 2 may be selected to form N-nitrosamines containing at least two N-nitrosamine groups, which allows for the preparation of energetic material precursors for highly nitrated nitramines.

[0019] A further aspect of the present invention provides a method for the synthesis of N-nitramines by an electrochemical continuous flow process, the method comprising: v) preparing a compound of formula II by any method, or more preferably by any method as defined herein above.

[0020] [ka]

[0021] forming an N-nitrosamine represented by the formula: vi) continuous flow electrochemical oxidation of the compound of formula II to form a compound of formula III

[0022] [ka]

[0023] (In the formula, R 1 and R 2 is as described above.) forming an N-nitramine compound represented by the formula: Includes:

[0024] Preferably, R of formula III 1 and R 2 were selected to form energetic N-nitramines containing at least two N-nitramine groups, such as RDX (cyclo-1,2,3-trimethylene-2,4,6-trinitramine, hexogen), HMX (cyclo-1,3,5,7-tetramethylene-2,4,6,8-tetranitramine, octogen), NTO (3-nitro-1,2,4-triazol-5-one), or CL-20 (2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane).

[0025] Nitramine compounds are those that contain at least one N-NO group. Heteroalicyclic nitramines have a ring containing the N-NO group. Such a ring may contain, for example, 2 to 10 carbon atoms and 2 to 10 ring nitrogen atoms.

[0026] Electrochemical oxidation is greener and more environmentally friendly, in line with the trend of developing green chemical synthesis.

[0027] Continuous flow chemical oxidation may be carried out by known methods, including: (1) dissolving and mixing a compound of formula II; (2) The reaction solution is pumped into a microchannel reactor equipped with electrodes for the electrolysis reaction, and the reaction product is collected to obtain a solution containing the compound represented by formula III.

[0028] Common anions for oxidation used as supporting electrolytes can be perchlorate, hexafluorophosphate, tetrafluoroborate, or nitrite, because they have high discharge potentials (potentials at which the anion is oxidized at the electrode). Regarding cations, their selection becomes more important when cathodic reduction is performed. The cationic moiety can be tetraalkylammonium, lithium, sodium, or magnesium ions.

[0029] Preferably, in step (2), the microchannel reactor equipped with electrodes comprises a syringe pump, a microchannel reactor, a negative electrode sheet, a positive electrode sheet, and a receiver, and both sides of the microchannel reactor are equipped with cathode and anode sheets, respectively; the syringe pump, the microchannel reactor, and the receiver are connected in series; and this connection is made by a pipeline.

[0030] More preferably, the positive electrode sheet may be a carbon sheet electrode, and the negative electrode sheet may be a platinum-plated electrode.

[0031] A further aspect of the present invention provides a method for the electrochemical continuous flow nitrosylation of amines for the synthesis of N-nitrosamines, the method comprising: xi) preparing an input flow reagent A in a first solvent; xii) preparing an input flow reagent B, which is an aqueous nitrite solution; xiii) introducing the input flow reagents A and B at a predetermined flow rate into a continuous electrochemical flow reactor equipped with electrodes for electrolysis to produce a reaction solution containing N-nitrosamines; Includes:

[0032] A further aspect of the present invention provides a method for the synthesis of N-nitramines by an electrochemical continuous flow process, the method comprising: xv) selecting the N-nitrosamine in the first solvent; xvi) continuous flow electrochemically oxidizing the N-nitrosamine in the first solvent to form an N-nitramine; Includes:

[0033] experiment General All chemicals were purchased from Acros Organics, Alfa Aesar, Apollo Scientific Ltd, Fisher Scientific Ltd, Scientific Laboratory Supplies Ltd, Merck KGaA, Fluorochem Ltd, and Sigma-Aldrich. All purchased chemicals were used without further purification. Deuterated solvents for NMR analysis were purchased from Sigma-Aldrich. A reference electrode kit was purchased from Osilla Ltd. Room temperature (rt) refers to 20-25°C. Thin-layer chromatography (TLC) experiments were performed on silica (TLC Silica Gel 60 F) purchased from Merck. 254 )-coated aluminum plates and visualized by UV light. Column chromatography was performed using silica gel (technical grade, 60 Å pore size, 230-400 mesh particle size, 40-63 μm particle size) purchased from Sigma-Aldrich, or by flash column chromatography on a Biotage® Isolera™ Four system using Biotage® SNAP Ultra 25 g or 50 g or Biotage® Sfaer Silica D 25 g or 50 g cartridges.

[0034] Electrolysis: Flow electrochemistry experiments were performed using an integrated Vapourtec Ion Electrochemical Reactor for heating experiments or a stand-alone Vapourtec Ion Electrochemical Reactor with an Aim-TTi EX354RD Dual Power Supply from Thurlby Thandar Instruments Ltd. Chemyx Fusion 100 Touch Syringe Pumps were used for the flow setup. Electrode materials employed were graphite (Gr), platinum (Pt), nickel (Ni), stainless steel (SS), and copper (Cu) purchased from Goodfellow, and boron-doped diamond (BDD) purchased from Vapourtec. Electrodes (5 × 5 cm 2 ) were separated by a 0.5 mm FEP spacer or a 1.0 mm PTFE spacer, each measuring 12 cm 2 Reactor volumes of 0.6 mL or 1.2 mL with exposed electrode surface areas of 0.6 mL or 1.2 mL were obtained.

[0035] General flow electrolysis procedure A: [ka]

[0036] A Vapourtec Ion Electrochemical Reactor (FEP spacer = 0.5 mm, reactor volume = 0.6 mL) was used, employing a graphite electrode as the anode and a nickel electrode as the cathode (active surface area = 12 cm for each electrode). 2 Electrolysis was performed in a non-divided cell. Solutions of a secondary amine (0.2 M, 1 equiv.) in acetonitrile and sodium nitrite (1.0 M, 5 equiv.) in distilled water were pumped into the electrochemical reactor at a flow rate of 0.025 mL / min (combined flow rate of 0.05 mL / min) and electrolyzed under constant current conditions (50 mA, 1.25 F). The first 1.5 reactor volumes were discarded to ensure the system reached steady state. After a known recovery time, the reaction mixture was diluted with 1% HCl. (aq)The mixture was treated with HCl and the aqueous phase was extracted with dichloromethane (3 x 25 mL). The organic layers were combined, dried over MgSO, filtered, and the solvent was removed in vacuo to give the crude product, which was purified by column chromatography.

[0037] In certain cases, to overcome solubility issues, procedure A was adapted by combining the two solutions into one syringe. NOTE: The combined solution in the syringe is pumped at a flow rate of 0.05 mL / min.

[0038] Procedure A was adapted for piperazine by electrolyzing the substrate under constant current conditions (100 mA, 1.25 F) using sodium nitrite in water (2.0 M, 10 equiv.) and an aqueous-only system to avoid the formation of a two-phase system.

[0039] N-nitrosylation N-nitrosylation flow electrochemical experiments were carried out at room temperature in an undivided commercial flow electrochemical reactor. Constant current conditions were applied, and the electrodes were separated using 500 μm FEP spacers, with a reactor volume of 0.6 mL and an active surface area of ​​each electrode of 12 cm. 2 A channel was fabricated using a nitrite-containing electrochemical device. N-methylbenzylamine (1a) was the substrate used for the reaction optimization required for its electrolysis to N-nitrosamine 1c (Figure 1). Sodium nitrite was chosen as the source of nitrite ions because it is significantly cheaper than potassium nitrite. Nitrite is insoluble in organic solvents, so water must be used as the solvent for sodium nitrite. In contrast, secondary amines were dissolved in water-miscible organic solvents, such as acetonitrile. The electrical conductivity of nitrite in solution, as well as the small electrode distance, allow for the omission of the use of an additional supporting electrolyte.

[0040] First, the reactor was equipped with Pt as the cathode and Gr as the anode, and 1.2 equivalents of NaNO2 was used at an applied charge of 2 F and a flow rate of 0.05 mL / min, affording the desired product 1c in 15% yield (Figure 1, entry 1).

[0041] Next, changing the nature of the cathode material from Pt to the less expensive Ni did not decrease the yield (Figure 1, entry 6). Tests of other cathode materials resulted in yields of 73% (SS), 67% (Cu), and 25% (Gr) (Figure 1, entries 3-5). Ni was chosen as the cathode material because it is significantly cheaper than Pt.

[0042] Increasing the initial concentrations of 1a and 1b from 0.14 M and 0.71 M to 0.2 M and 1.0 M slightly reduced the yield of 1c to 81% (Figure 1, entry 9). However, at the increased concentrations, decreasing the applied charge from 1.75 F to 1.25 F increased the yield of 1c to 89% (Figure 1, entry 10).

[0043] See Figure 2. Under optimized conditions, this procedure was applied to convert various cyclic and acyclic aliphatic secondary amines to their corresponding N-nitrosamines (Figure 2). Starting with N-methylbenzylamine, increasing the steric bulk to N-ethyl, N-isopropyl, and N-tert-butyl amines gave good to excellent yields (2a–2d), although the yield decreased with increasing steric bulk. Dibenzylamine produced the product in an impressive 92% yield (2e). This method was also effective for piperidine and its 4-substituted derivatives, as the products were obtained in 68%–99% yields (2f–2k). cis-2,6-dimethylpiperidine and 2,2,6,6-tetramethylpiperidine gave products 2l and 2m in 68% and 72% yields, respectively. Mono-N-substituted piperazine derivatives were successfully nitrosated at the other nitrogen atom, giving products in good to excellent yields (2n, 2o, and 2q), except for 1-phenylpiperazine, which gave product 2p in only a moderate yield of 46%. Piperazine was dinitrosated in a low yield of 30% (2r), but this reaction was carried out using water as the sole solvent due to the formation of a biphasic system in the standard solvent system. Pyrrolidine and azepane were used as five- and seven-membered ring amines, giving products in good yields of 75% (2s and 2t). Morpholine and thiomorpholine gave nitrosated products in 78% and 63%, respectively (2u and 2v). Fused bicyclic ring compounds such as cis-octahydroisoindole and 1,2,3,4-tetrahydroisoquinoline gave products in 54% and 83%, respectively (2w and 2x). Furthermore, several acyclic symmetric aliphatic amines, such as dicyclohexylamine, diisopropylamine, and dibutylamine, produced N-nitrosated amines in low to moderate yields (2y-2aa).

[0044] Product characterization A selection of characterization data is provided below. N-Nitroso-N-methylbenzylamine (2a) [ka]

[0045] Prepared over 1.5 h from N-methylbenzylamine (54.5 mg, 58.0 μL, 0.45 mmol) according to general procedure A. The product was obtained as a yellow oil (61.7 mg, 0.41 mmol, 91%). 1 H NMR(500MHz,CDCl3):δ7.41-7.26(m,4.60H),7.14-7.13(m,0.46H),5.31(s,1.55H), 4.81(s,0.44H),3.69(s,0.66H),2.95(s,2.34H). 13 C NMR(126MHz,CDCl3):δ134.5,133.8,129.2,129.0,128.7,128.5,128.2,128.1,57.8, 48.0, 38.6, 31.1. HRMS(CI): m / z [M+H] of CHON + Calculated value 151.08659, measured value 151.0865.

[0046] Two configurational isomers resulting from restricted rotation around the NN moiety double bond were observed in the NMR spectrum in a ratio of 2:7. The NMR data are identical to the literature data.

[0047] N-Nitrosodicyclohexylamine (2y) [ka]

[0048] Prepared over 4 h from dicyclohexylamine (217.6 mg, 1.20 mmol) according to general procedure A. The crude product was purified by column chromatography on silica gel (DCM:cyclohexane=3:7) to give 2y (140.9 mg, 0.67 mmol, 56%) as yellow crystals. 1H NMR (500MHz, CDCl3): δ4.87(tt,J=11.7,3.7Hz,1H),3.71(tt,J=11.0,4.5H z,1H),1.96-1.57(m,12H),1.47-1.20(m,7H),1.14(qt,J=12.9,3.6Hz,1H). 13 C NMR (126MHz, CDCl3): δ58.7,52.3,34.5,29.5,26.2,25.6,25.5,25.4. HRMS(CI): m / z [M] of C12H22ON2 + Calculated value 210.17266, measured value 210.1727.

[0049] The NMR data are identical to the literature data.

[0050] In-line purification General flow electrolysis procedure B: [ka]

[0051] This procedure is similar to Procedure A above, except that it uses a second pump connected through a T-piece that is used to protonate the remaining starting material and capture excess NaNO and its intermediates, and a third pump connected through another T-piece that is utilized for extraction of the product into an organic layer, where the layers are separated with an in-line liquid-liquid separator. After recovery for a known period of time, the solvent is removed in vacuo to yield the pure product.

[0052] An in-line purification method based on acid post-treatment was devised. This was achieved by including a commercially available in-line liquid-liquid extractor. 1% HCl (aq) was pumped through the system to ensure that unreacted starting materials, excess NaNO, and materials resulting from the electrolysis of NaNO remained in the aqueous phase. Dichloromethane was then used to extract the N-nitrosamines from the aqueous phase, and the two different solvent streams were separated in an extractor.

[0053] Nitrosyl to Nitro Conversion - A Single-Step Synthesis [ka]

[0054] [Table 1]

[0055] At a very low flow rate of 0.05 mL / min, a back pressure of 1 bar cannot be achieved. Similarly, at 0.01 mL / min, a back pressure of 2 bar cannot be achieved. Therefore, a flow rate of 0.2 mL / min was used to investigate the effect of back pressure on the system. As can be seen from Table 1, the effect of back pressure had little effect on the yield of 2a. Preferably, there is no back pressure regulator.

[0056] The effects of different anode and cathode materials were tested on their efficiency, and the results are shown in Table 2. Changing the anode from platinum (entry 1) to glassy carbon (GC) (entry 2) and graphite (entry 3) showed higher product yields with Pt and GC anodes, while less decomposition occurred with Graphite. Therefore, graphite is the preferred anode material. Furthermore, changing the cathode from platinum to nickel (entry 4), copper (entry 5), and stainless steel (entry 6) showed similar product and reactant yields with platinum, nickel, and copper. Metal cathodes may be selected so that O2 is efficiently chemisorbed onto the surface. The energy of this process should be approximately -0.5 to -2 eV, which can be achieved with many metals. Platinum, gold, and silver are further suitable cathode materials.

[0057] [ka]

[0058] [Table 2]

[0059] Increasing the O2 flow rate was investigated. O2 was flowed at two and four times the liquid flow rate to see if an excess flow of oxygen gas could convert more starting material. However, in all cases, the yields of starting material and product were similar, indicating that flowing excess gas did not affect the results. This is beneficial because reducing the gas flow is more cost-effective.

[0060] The applied charge was varied from 1 F / mol to 2 F / mol in increments of 0.25 F / mol. The best results were obtained with an applied charge of 1.25 F / mol, where 55% of the starting material was observed to be unreacted, resulting in a 21% yield of product. Higher charges resulted in slightly higher yields, but more decomposition was observed, thus indicating incompatibility with the system.

[0061] Finally, the concentration of the solution was reduced from 0.05 M to 0.025 M to see if this change would result in more conversion of the starting material and less decomposition, but the results of multiple experiments at these concentrations were nearly identical, indicating that this change did not affect the results.

[0062] The following reaction scheme was repeated to give compounds 2a-e shown in Figure 7 below. [ka]

[0063] Aspects of the present invention will now be described, by way of example only, with reference to the drawings, in which: [Brief explanation of the drawings]

[0064] [Figure 1] FIG. 1 shows a table of results for N-nitroso-N-methylbenzylamine. [Figure 2] FIG. 2 shows a table of example N-nitrosamines that have been synthesized. [Figure 3] FIG. 3 shows the optimization of nitrite. [Figure 4]Figure 4 shows the optimization of NaNO2. [Figure 5] FIG. 5 shows the optimization of the solvent and anode material. [Figure 6] FIG. 6 shows the synthesis of N-nitramines in a multi-step synthesis. [Figure 7] FIG. 7 shows the synthesized N-nitrosamines. DETAILED DESCRIPTION OF THE INVENTION

[0065] Figures 1 and 2 are considered in the experiment.

[0066] Figure 3 shows the different yields of various nitrites, and advantageously, the inexpensive sodium nitrite gave superior yields compared to the other nitrites, but other nitrites, especially the metal nitrites, also gave similar results.

[0067] FIG. 4 shows that increasing the concentration of sodium nitrite increased the yield.

[0068] Figure 5 shows that alternative polar solvents work, but the less hazardous MeCN is well suited for large-scale production. Alternative carbon-based electrodes have produced results, with graphite providing the best yields in comparative studies.

[0069] Figure 6 shows a two-step route for the conversion of amines to nitramines for the synthesis of energetic materials.

[0070] FIG. 7 shows the electrochemical oxidation of a nitrosylated amine to the corresponding nitramine.

Claims

1. 1. A method for the electrochemical continuous flow nitrosylation of amines for the synthesis of N-nitrosamines, comprising: i) Formula (I) 【Chemistry 1】 (In the formula, R １ and R ２ are independently selected from H, alkyl, aryl, phenyl, cycloalkyl, heterocyclic rings, and aromatic heterocyclic rings, or are taken together to form a heterocyclic ring or an aromatic heterocyclic ring; ii) preparing an input flow reagent B, which is an aqueous nitrite solution; iii) The input flow reagents A and B are introduced at a predetermined flow rate into a continuous electrochemical flow reactor equipped with electrodes for electrolysis, and a reaction mixture of formula II is obtained. 【Chemistry 2】 producing a reaction solution containing an N-nitrosamine represented by the formula: A method comprising:

2. 2. The method of claim 1, wherein the nitrite is tetrabutylammonium nitrite, a Group I metal nitrite, or a Group II metal nitrite.

3. 3. The method of claim 1, wherein the first solvent is a polar organic solvent.

4. 4. The method of claim 3, wherein the solvent is MeCN or MeOH.

5. 10. The method of any one of the preceding claims, wherein the anode is BDD or graphite and the cathode is platinum.

6. 10. The method according to any one of the preceding claims, wherein the reaction solution is washed with dilute acid (step iv).

7. 10. The method of any one of the preceding claims, wherein the amine compound of formula (I) is in a solution of 0.01M to 5M.

8. 10. The method of any one of the preceding claims, wherein the aqueous nitrite solution is a 0.01M to 5M solution.

9. 10. The method of any one of the preceding claims, wherein the concentration of the aqueous nitrite solution is at least twice the concentration of the amine compound of formula (I).

10. R of Formula II １ and R ２ 4. The method of any one of the preceding claims, wherein:

11. A method for synthesizing N-nitramines by an electrochemical continuous flow process, comprising: v) a method according to any one of the preceding claims, wherein the compound of formula II 【Transformation 3】 forming an N-nitrosamine represented by the formula: vi) continuous flow electrochemical oxidation of the compound of formula II to form a compound of formula III 【Chemistry 4】 (In the formula, R １ and R ２ are independently selected from H, alkyl, aryl, phenyl, cycloalkyl, heterocyclic, and heteroaromatic rings, or are taken together to form a heterocyclic or heteroaromatic ring; A method comprising:

12. R of Formula III １ and R ２ 4. The method of claim 3, wherein the N-nitramine is an energetic material comprising at least two N-nitramine groups.

13. 13. The method of claim 12, wherein the energetic substance is RDX, HMX, or CL20.

14. 1. A method for the electrochemical continuous flow nitrosylation of amines for the synthesis of N-nitrosamines, comprising: xi) preparing an input flow reagent A in a first solvent; xii) preparing an input flow reagent B, which is an aqueous nitrite solution; xiii) introducing the input flow reagents A and B at a predetermined flow rate into a continuous electrochemical flow reactor equipped with electrodes for electrolysis to produce a reaction solution containing N-nitrosamine; A method comprising:

15. A method for synthesizing N-nitramines by an electrochemical continuous flow process, comprising: xv) selecting the N-nitrosamine in the first solvent; xvi) continuous flow electrochemically oxidizing the N-nitrosamine in the first solvent to form an N-nitramine; A method comprising:

Images