Process Improvement for the Continuous Synthesis of N-Benzylhydroxylamine Hydrochloride

Abstract

N-Benzylhydroxylamine hydrochloride serves as a critical intermediate in organic synthesis, yet traditional synthesis methods often face significant safety risks and high production costs. In this work, we developed a continuous synthesis process for N-benzylhydroxylamine hydrochloride, achieving an overall yield of 75% under mild and safe reaction conditions. Additionally, the implementation of solvent recovery and the recycling of hydroxylamine hydrochloride reduced the production cost to approximately $10 per kilogram. These advancements underscore the economic and practical viability of this method for large-scale industrial applications.

1. Introduction

N-Benzylhydroxylamine hydrochloride is a pivotal intermediate in organic synthesis, widely utilized in pharmaceutical synthesis. N-benzylhydroxylamine can undergo Michael addition and cyclization with unsaturated esters (alkenoates) to generate azoldone, which then proceeds hydrogenation to give β-amino acids [1,2]. It can also undergo condensation with aldehydes or ketones to generate N-benzyl nitrones, which serve as precursors for the efficient construction of isoxazoline frameworks via 1,3-dipolar cycloaddition reactions [3,4,5,6]. Isoxazolidines are vital structures in the field of drug discovery, resembling a diverse array of natural building blocks and demonstrating a wide range of promising biological activities [7,8]. Notably, N-benzylhydroxylamine hydrochloride is a crucial precursor in the synthesis of aminocyclopentanol, an intermediate for the production of Ticagrelor (as illustrated in Figure 1) [9]. Ticagrelor, a novel antiplatelet agent, has demonstrated superior efficacy over clopidogrel in reducing the occurrence of cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome. The current synthesis method of ticagrelor, utilizing N-benzylhydroxylamine, is one of the most economically efficient approach. Consequently, the development of a safe, cost-effective, and operationally simple production process is of considerable significance.

It was found that N-benzylhydroxylamine hydrochloride could usually be prepared via several different routes as shown in Figure 2. In the laboratory, N-Benzylhydroxylamine could be prepared from the reduction of benzaldehyde oxime, which could be synthesized by the condensation of benzaldehyde and hydroxylamine hydrochloride [10,11]. However, the use of a high-cost reducing agent, sodium cyanoborohydride (price: ~300 $/kg), in the reduction step limited the industrial application of this protocol. In addition, the hydrolysis of N-benzyl-N-benzylideneamine oxide in hydrochloric acid could also afford N-benzylhydroxylamine hydrochloride in high yield, while the oxidation of dibenzylamine with hydrogen peroxide often suffered from the explosion risk [12,13,14]. To be noted, the substitution reaction of benzyl chloride and hydroxylamine hydrochloride under excessive amounts of base and high temperature seems to be an attractive pathway to give N-benzylhydroxylamine hydrochloride, considering the low cost and readily available starting materials [15]. This route was also found to be used in industry. However, The problem is that hydroxylamine could be easily decomposed under high temperatures, which results in low yield and explosion risk [16,17]. In 2018, Lebel and co-workers developed a general in-line procedure for the synthesis of amines from alkyl halides and hydroxylamine in continuous flow, and reported that N-benzylhydroxylamine could be produced in 65% yield from benzyl chloride and hydroxylamine, which sounds promising for industrial applications [18]. Lebel’s continuous method shows promise for large-scale industrial applications. However, the use of excess hydroxylamine (150 equivalents) increases production costs, and the unreacted hydroxylamine poses a safety risk under the reaction conditions (100 °C).

Continuous-flow reactors, also known as microreactors, are playing an increasingly important role in the pharmaceutical industry [19,20,21,22]. Compared with batch reactors, it offers advantages such as excellent heat and mass transfer, easy manipulation of gas, and accelerated reaction rate. In the synthesis process of N-benzylhydroxylamine hydrochloride, the use of hydroxylamine is required for the substitution reaction pathway, which presents an explosion risk under high temperatures. Compared to traditional batch reactors, the use of a continuous reactor can efficiently reduce the safety risks and improve the reaction efficiency. Although in Lebel’s general procedure, N-Benzylhydroxylamine was prepared from benzyl chloride and hydroxylamine in the continuous-flow reactor, the moderate yield, only 65%, leaves enough space to be improved for industrial applications. Herein, we carried out a detailed conditional optimization for the synthesis of N-benzylhydroxylamine hydrochloride from benzyl chloride and hydroxylamine through the use of a continuous-flow reactor, which aimed at higher yield, low reaction temperature, and decreased waste production.

2. Materials and Methods

2.1. Materials and Equipments

Hydroxylamine hydrochloride, sodium hydroxide, ethyl acetate, and methanol were purchased from Huihong (Changsha, China). Hydroxylamine aqueous solution (50%) and benzyl chloride were purchased from Titan (Shanghai, China). All the chemicals and reagents were of analytical grade and were used as received without further purification.

Microchannel reactor (also known as continuous flow reactor) and its auxiliary equipment, G1 type, equipped with 10 glass/silicon carbide modules, module liquid storage capacity 8.2 mL, were purchased from Corning (Changzhou, China).

2.2. Experimental Details

2.2.1. The Flow Reaction Process

Preparation of material A: add 63 g of benzyl chloride to a 2 L beaker, then add methanol to give a 1000 mL solution with a concentration of 0.5 mol/L.

Preparation of material B: in a 2 L beaker, add 800 mL of methanol and 200 mL of water. Then, under stirring, add 139 g hydroxylamine hydrochloride, then slowly add 80 g sodium hydroxide, and use ice water bath to ensure that the internal temperature is not higher than 20 °C. Stir the mixture at 10–20 °C for 30 min and filter out the sodium chloride. This process results in the preparation of a 1000 mL hydroxylamine solution with a concentration of 2.0 mol/L.

The optimal reaction setup: the reactor temperature was set to 60 °C, and the pressure was maintained at 8 bar. Two independent plunger pumps were used to inject the materials, with a flow rate of 5.0 mL/min. Pump 1 injected material A, which entered Module 1 for preheating. Pump 2 injected material B, which was mixed with material A in Modules 1 and 2. Modules 2–10 served as reaction modules, with the reaction mixture being collected at the outlet after a residence time of 7.38 min. The configuration of the continuous flow reactor is shown in Figure 3.

Post-reaction processing: after the reaction mixture was cooled to room temperature, the pH was adjusted to 4–5 using 10% hydrochloric acid. The methanol solvent was then recovered by reduced pressure distillation. To the resulting solid, 200 mL of water was added, and the mixture was extracted three times with 200 mL of ethyl acetate. The organic phases were combined and dried using anhydrous Na₂SO₄. After concentration, 68 g of N-benzylhydroxylamine hydrochloride was obtained, corresponding to a yield of 85%. The purity of the liquid was 75.17%, with dibenzyl-substituted impurities present at 17.21% [23]. The purity mentioned herein refers to the percentage of the area of the substance measured by the area normalization method in the liquid chromatography.

2.2.2. Purification by Crystallization

The crude product was transferred to a 1 L flask, and 540 mL of ethyl acetate (at a ratio of 1 g per 8 mL) was added. The mixture was heated to reflux at 70 °C. After the addition of 3.4 g activated carbon for decolorization, the solution was filtered on vacuo while still hot. The filtrate was then slowly cooled to crystallize at a temperature between 0 °C and −5 °C. The wet product was isolated by pumping and filtration on vacuo. After drying in an air oven at 45 °C for 8 h, 60 g of N-benzylhydroxylamine hydrochloride was obtained, with a separation yield of 89%. The purity of the liquid phase was 99.82%, and the amount of dibenzyl-substituted impurity was 0.15%.

2.2.3. Recycling Use of Hydroxylamine Hydrochloride

To recycle hydroxylamine hydrochloride, 290 mL of purified water was added to the aqueous phase obtained after the extraction of N-benzylhydroxylamine hydrochloride. This aqueous solution was then mixed with 800 mL of methanol, followed by the addition of 73 g of hydroxylamine hydrochloride. After dissolving, 80 g of sodium hydroxide was added, and the solution was stirred at 10–20 °C. Next, the mixture was filtered to remove sodium chloride, and the resulting solution was prepared as material B. The subsequent operations followed the procedure described in Section 2.2.1.

2.2.4. Calculation of the Recycling Rate of Hydroxylamine Hydrochloride

The aqueous phase from the extraction of N-benzylhydroxylamine hydrochloride was concentrated under reduced pressure to obtain a white solid. This solid was then extracted with 200 mL of methanol and concentrated under reduced pressure again to yield hydroxylamine hydrochloride. After drying the solid in an air oven at 45 °C for 8 h, 66 g of hydroxylamine hydrochloride was recovered, resulting in a recovery rate of 47%.

3. Results & Discussion

3.1. Condition Optimization of the Continuous-Flow Reaction

Currently, two types of hydroxylamine are available: hydroxylamine hydrochloride and aqueous hydroxylamine solution. The latter is classified as an explosive hazardous material, which is difficult to be purchased from the market. Therefore, hydroxylamine hydrochloride was selected as the starting material. It was neutralized with sodium hydroxide to produce a hydroxylamine methanol solution. Initially, 5.0 equivalents of hydroxylamine hydrochloride were employed. To mitigate the risk of thermal explosion associated with hydroxylamine, milder reaction conditions were chosen. Specifically, a temperature of 60 °C and a pressure of 8.0 bar were applied. Surprisingly, TLC analysis showed that under these conditions, benzyl chloride reacted completely, primarily yielding N-benzylhydroxylamine, with only a small amount of dibenzyl-substituted impurities. Due to the lower polarity of these impurities, the crude product was recrystallized with ethyl acetate, which effectively removed most of the impurities. A highly pure N-benzylhydroxylamine hydrochloride was obtained with an overall yield of 76% (

Table 1. Process Optimization for the Synthesis of N-Benzylhydroxylamine Hydrochloride.

Entry	Hydroxylamine Hydrochloride/ Equiv.	Reaction Temperature/°C	Flow Rate of Benzyl Chloride/ mL*min−1	Flow Rate of Hydroxylamine/ mL*min−1	Concentration of Benzyl Chloride/ mol*L−1	Crystallization Yield/% 1
1	5.0	60	5.0	5.0	0.1	76
2	4.0	60	5.0	5.0	0.1	74
3	3.0	60	5.0	5.0	0.1	64
4	1.5	60	5.0	5.0	0.1	32
5	5.0	80	5.0	5.0	0.1	77
6	5.0	40	5.0	5.0	0.1	nr
7	5.0	60	10.0	10.0	0.1	37
8	5.0	60	4.0	4.0	0.1	78
9	5.0	60	3.0	3.0	0.1	82
10	5.0	60	5.0	5.0	0.3	77
11	5.0	60	5.0	5.0	0.5	77
12	5.0	60	5.0	5.0	1.0	77
13	4.0	60	5.0	5.0	0.5	75

¹ yield of N-benzylhydroxylamine hydrochloride after recrystallization in ethyl acetate.

, Entry 1).

When the amount of hydroxylamine hydrochloride was further reduced to 4.0 equivalents, the crystallization yield of N-benzylhydroxylamine hydrochloride remained high at 74% (Table 1, Entry 2), which is comparable to the yield achieved with 5.0 equivalents. However, when the amount was reduced to 3.0 equivalents or 1.5 equivalents, the overall yield of N-benzylhydroxylamine hydrochloride declined significantly. TLC analysis revealed the presence of considerable dibenzyl-substituted byproducts and unreacted benzyl chloride (Table 1, Entries 3 and 4). N-benzylhydroxylamine could react with benzyl chloride, leading to the formation of dibenzyl-substituted byproducts, while increasing the amount of hydroxylamine helps to suppress this side reaction. Based on these results, 4.0 equivalents of hydroxylamine hydrochloride were chosen as the optimal amount.

Next, during the screening of the reaction temperature, it was observed that increasing the temperature to 80 °C did not significantly improve the reaction yield (Table 1, Entry 5), while lowering the temperature to 40 °C led to a substantial decrease in reaction conversion (Table 1, Entry 6). Therefore, considering both safety concerns and reaction yield, the temperature was ultimately set at 60 °C.

For the flow rate conditions, increasing the flow rate of benzyl chloride to 10.0 mL/min resulted in a decrease in reaction conversion due to insufficient residence time, with TLC analysis showing significant amounts of unreacted benzyl chloride remained (Table 1, Entry 7). When the flow rate was further reduced to 4.0 mL/min and 3.0 mL/min, the yield of N-benzylhydroxylamine hydrochloride increased slightly (Table 1, Entries 8 and 9). However, a slow flow rate led to clogging issues in the G1 microchannel reactor. As a result, a flow rate of 5.0 mL/min was maintained in subsequent experiments to avoid blockages.

To increase production capacity, the concentration of the reactants was further increased to 0.3 mol/L and 0.5 mol/L. However, the crystallization yield of N-benzylhydroxylamine hydrochloride remained essentially unchanged (Table 1, Entries 10 and 11). When the concentration was further increased to 1.0 mol/L, a blockage occurred near the end of the G1 microchannel reactor (Table 1, Entry 12). This was attributed to the final module in the original design, which was a cooling module using circulating water. Replacing it with a heating module helped alleviate the blockage issue. Considering all factors, a material concentration of 0.5 mol/L was selected for the final process.

Based on the above experimental results, the final continuous process was determined as follows: 4.0 equivalents of hydroxylamine hydrochloride were used at a temperature of 60 °C and a pressure of 8 bar. Benzyl chloride, with a concentration of 0.5 mol/L, and hydroxylamine, with a concentration of 2.0 mol/L, were pumped into the continuous reactor at a flow rate of 5.0 mL/min. The reaction proceeded through 1 preheating module and 9 reaction modules, with a total residence time of 7.38 min to complete the reaction.

3.2. The Recycling of Hydroxylamine Hydrochloride

The continuous process for synthesizing N-benzylhydroxylamine hydrochloride employs 4 equivalents of hydroxylamine hydrochloride. The aqueous phase generated during post-treatment contains a high concentration of ammonia nitrogen, which increases the cost of the water-water process. Thus, it is necessary to facilitate the recycling of hydroxylamine hydrochloride during the reaction process. This can be achieved by exploiting the difference in solubility between N-benzylhydroxylamine hydrochloride and hydroxylamine hydrochloride. Initially, ethyl acetate is used to extract N-benzylhydroxylamine hydrochloride from the aqueous phase. The resulting aqueous phase is then concentrated under reduced pressure, and hydroxylamine hydrochloride is extracted with methanol, achieving a recovery rate of 47%. To streamline the process, the aqueous phase is directly reused in the next continuous reaction, with water and hydroxylamine hydrochloride added as needed (as shown in

Table 2. The recycling use of hydroxylamine hydrochloride.

Entry	Number	Input of Hydroxylamine Hydrochloride	Yield of N-Benzylhydroxylamine Hydrochloride/%	Purity of N-Benzylhydroxylamine Hydrochloride/%
1	0	139 g	75	99.82
2	1	73 g + Recovered water phase	75	99.79
3	2	73 g + Recovered water phase	75	99.83
4	3	73 g + Recovered water phase	75	99.59

, recovered water phase indicates the aqueous phase from the previous experimental cycle). The purity and yield of N-benzylhydroxylamine hydrochloride in subsequent reactions remain stable, confirming the effectiveness of the recycling process. After reusing the recovered hydroxylamine hydrochloride aqueous phase twice, the reaction yield continues to be consistent, demonstrating that the hydroxylamine hydrochloride recycling process is feasible and efficient.

4. Conclusions

A one-step synthesis process for N-benzylhydroxylamine hydrochloride was optimized using continuous synthesis technology, with benzyl chloride and hydroxylamine hydrochloride as raw materials. The effects of material equivalents, reaction temperature, feed flow rate, and material concentration were systematically investigated. Under the optimal conditions, the overall yield reached 75%. Compared to previous synthetic routes, this method significantly reduces the amount of hydroxylamine hydrochloride required. Additionally, the reaction conditions are mild, the reaction time is short, and the risk of thermal explosion associated with high-temperature hydroxylamine is effectively avoided. Furthermore, the process addresses the environmental concerns related to the “three wastes” (wastewater, waste gas, and solid waste), making it a promising solution for industrial-scale applications. In future research, the microchannel reactor system is hoped to be extended to other high-risk synthesis reactions, leveraging its high selectivity and conversion efficiency to prepare a broader range of valuable compounds.

5. Patents

CN116239492; Continuous synthesis process of N-benzylhydroxylamine hydrochloride. CNIPA: Beijing, China, 2009. was resulting from the work reported in this manuscript.