Jinpei Huang,Xingwei Lu,Xuejing Zhang,Yiqiang Jin,Yifeng Zhou,

1 College of Life Science, China Jiliang University, Hangzhou 310018, China

2 Apeloa Pharmaceutical Co., Ltd., Dongyang 322118, China

Keywords:Multiphase reaction Microreactor Synthesis Oxaziridine Process intensification

ABSTRACT 1-Oxa-2-azaspiro[2.5]octane,as one of N-H oxaziridines,is a selective electrophilic aminating agent for N-,S-,C-,and O-nucleophiles.It has the features of stereoselectivity and the absence of formation of strongly acidic or basic byproducts,leading to considerable interest in the development of organic synthetic methods.Currently,the economically feasible route of production of 1-oxa-2-azaspiro[2.5]octane is the reaction of cyclohexanone with ammonia and sodium hypochlorite.However,due to strong exothermic reactions,massive gas release and heterogeneous reaction,the controllability,efficiency and safety of the reaction are in great difficulty using batch technology.In this paper,a microreaction system containing predispersion,reaction and phase separation was introduced into the preparation of 1-oxa-2-azaspiro [2.5] octane.The research results showed that precise control of the process including droplet dispersion,temperature control,reaction time control and fast continuous phase separation,was the key to process intensification.Under optimal conditions,the concentration of 1-oxa-2-azaspiro[2.5]octane in product obtained by microreaciton system(～2.0 mol·L-1)was much higher than that obtained by batch technology(0.2-0.4 mol·L-1),which demonstrated that the continuous-flow synthesis would be a more efficient substitute for batch synthesis.Meanwhile,the results of the derivation experiments also showed that the aminating agent solution with higher concentration was more advantageous in the applications.

1.Introduction

Oxaziridines are a class of multifunctional oxidants characterized by the existence of two electronegative heteroatoms in the strained three-membered ring.They are usually used in organic synthesis as atom-transfer reagents,for instance,oxidations or aminations of N-,S-,C-,and O-nucleophiles [1-5].The reaction processes involved oxaziridines are driven by the release of ring strain and the formation of a strong carbonyl,imine or oxometal π-bond[6].As a result,reactions mediated by these reagents have characteristic features of stereoselectivity and absence of formation of strongly acidic or basic byproducts.Oxaziridines can be conveniently classified on the basis of the identity of their N-substituents,which play a significant role in their reactivity and stability.Among them,N-H oxaziridines usually have higher reactivity and lower synthetic cost.However,they have been exploited rarely in organic synthesis because of their perceived poor stability [7].

The research object in this paper,1-oxa-2-azaspiro[2.5]octane,is one of N-H oxaziridines,which is a selective electrophilic aminating agent [8,9].Due to the instability of N-H imine,the 1-oxa-2-azaspiro[2.5]octane which needs to be stored and used in solution form can not be synthesized by standard peracid oxidation methods [10].Schmitzet al.[11] reported the preparation of 1-oxa-2-azaspiro [2.5] octane by reaction of cyclohexanone with hydroxylamine-O-sulfonic acid and sodium hydroxide.As shown in Fig.1,hydroxyamine-O-sulfonic acid first undergoes an addition reaction with a carbonyl group and the N atom is attached to theCatom to form an active intermediate.Then,ring closure occurs by an intramolecular nucleophilic attack on the N atom after deprotonation of the hydroxyl group attached to the C atom.Ultimately,one hydrogen sulfonate radical is removed to give 1-oxa-2-azaspiro[2.5]octane.Although there are few impurities in the final purified solution,the reagents used in this synthetic route are costly,and the yield is relatively low due to the rapid deterioration of the product under strong alkali condition.Subsequently,the same research team developed another synthetic route to obtain 1-oxa-2-azaspiro [2.5] octane by reaction of cyclohexanone with ammonia and sodium hypochlorite[12].The reactive intermediate monochloramine obtained from the reaction of ammonia and sodium hypochlorite,reacts with cyclohexanone to give 1-chloroa minyl-1-hydroxycyclohexane(Fig.1).And subsequent intramolecular action removes one molecule of hydrogen chloride to give 1-oxa-2-azaspiro [2.5] octane.A small amount ofN-chlorocyclohexanimine is formed in this reaction,but it does not affect typical synthetic applications of oxaziridine.Although this new synthetic route partly solved the cost problem,other problems remain,such as violent side reactions,massive release of gas,and strongly exothermic process.Calorimetric measurements revealed a 366 kJ·mol-1exotherm for the overall reactions,which translated to a potential adiabatic heat rise of 45°C.In batch reactors,even with the slow addition of sodium hypochlorite,there will still be cases where the local temperature of the reaction mixture is too high leading to a reduced yield,and the generation of large amounts of gas is prone to a safety problem.Moreover,since the reaction is heterogeneous,it is easy to have uneven dispersion of two phases and aggravation of side reactions during the scaleup.In general,the small batch production method was adopted,and the freshly prepared 1-oxa-2-azaspiro [2.5] octane is stored in toluene at a concentration of 0.2-0.4 mol·L-1[13],which is relatively low for use.

Fig.1.The different synthetic routes of 1-oxa-2-azaspiro [2.5] octane and their reaction mechanisms: (a) the reaction of cyclohexanone with hydroxylamine-Osulfonic acid and sodium hydroxide;(b) the reaction of cyclohexanone with ammonia and sodium hypochlorite.

To sum up,the second synthetic route has industrial application prospects,but at present,the traditional batch process still has many problems to be solved before large-scale production.Microreaction technology can realize better heterogeneous fluid mixing,and more accurately control various reaction parameters[14-21],so as to obtain more stable products with higher yield under safer and more efficient conditions.Our previous work proved the potential of microreaction technology for intensifying heterogeneous reaction processes such as diazotization [22],Friedel-Crafts reaction[23]and catalytic oxidation[24].Therefore,this paper aimed to use microreaction technology to solve the above problems.Due to the instability of the active intermediate monochloramine,we used the microreactor equipment to obtain the dispersion of the organic phase in aqueous ammonia first,and then rapidly mixed the dispersion with sodium hypochlorite.This scheme greatly improved the utilization rate of the active intermediate monochloramine,and effectively minimized side reactions caused by inadequate material mixing,local overheating,and the long reaction time.After optimization,the yield of the reaction and the concentration of oxaziridine in final purified solution was effectively improved.

2.Materials and Methods

2.1.Materials

Sodium hydroxide (≥96%,pellet,Greagent),hydrochloric acid(36%-38%,Greagent),sulphuric acid(95%-98%,Greagent),ammonium hydroxide solution (25%-28%,Greagent),cyclohexanone(≥99.5%,Greagent),toluene (≥99.5%,Greagent),acetic acid(≥99.8%,Greagent),sodium thiosulfate (0.1 mol·L-1,Greagent),magnesium sulfate (≥99.5%,Greagent),morpholine (≥99%,Greagent),sodium acetate(≥99.5%,Greagent),soluble starch(AR,Greagent),benzaldehyde (99%,Adamas),phenolphthalein (IND,Adamas),and potassium iodide (99%,Adamas) were purchased from Tansoole.Sodium hypochlorite (6%-14% active chlorine basis) was purchased from Aladdin.All reagents were not further purified before use.

2.2.Microreaction system

The microreaction system consisted of three units: predispersion,reaction and phase separation (Fig.2).Considering that the reaction between aqueous ammonia and sodium hypochlorite is violent,it is easy to cause side reactions to dominate.The following strategy was selected for the experiments: aqueous ammonia and organic phase were mixed to form a dispersion first,and then reacted with sodium hypochlorite.Three streams of raw material fluid were delivered to the system respectively by metering pumps(SZWEICO,2PB3020IV).Here,we used a micropore dispersion mixer (homemade [25-27],see the Supplementary Material for details) to achieve the predispersion of aqueous ammonia and toluene solution containing cyclohexanone.Subsequently,the heterogeneous dispersion was cooled and reacted with sodium hypochlorite solution in a printed micro-channel reactor (HZSS,WRC00820,Hastelloy).The reaction time can be adjusted by changing the number of series reactors (the internal volume of each reactor is 8.2 ml) and the total flow rate.The intergrated micro-channel reactor achieves efficient heat transfer with a heat transfer coefficient of up to 1500 W·m-2·K-1.The reaction liquid from the micro-channel reactor entered the glass phase separator,and then water,oil and gas were separated by gravity.The oil phase was washed with 0.1 mol·L-1hydrochloric acid and water,and then dried with magnesium sulfate.Finally,the product concentration (Coxa) was determined by redox titration [13] (see the Supplementary Material for details).

Fig.2.Schematic of the microreaction system.

2.3.Batch reaction process

A mixture containing toluene,cyclohexanone and aqueous ammonia was mixed in a 100 ml flask with cooling at 0°C.Sodium hypochlorite was added slowly.After about 30 s of reaction,the upper layer was washed with 0.1 mol·L-1hydrochloric acid and water,and then dried with magnesium sulfate.

3.Results and Discussion

3.1.Predispersion

Due to the obvious competition between main and side reactions,selective enhancement of the main reaction process is very important.Based on the fact that the main reaction is a twophase reaction while the leading side reaction is a aqueous phase reaction,increasing the contact area of the two phases is beneficial to the mass transfer process of the main reaction,so as to improve the reaction efficiency and selectivity.Here,aqueous ammonia was chosen to be the continuous phase,and the organic phase was chosen to be the dispersed phase.Since the flow rates of aqueous ammonia and organic phase relative to sodium hypochlorite were small,the mixing total flow velocity in a micropore dispersion mixer can be varied by varying aqueous ammonia concentration while keeping reagent equivalents constant,thus affecting the dispersion state.As shown in Fig.3,as the ammonia dilution increased (the flow rate of aqueous ammonia increased),the dispersion effect improved significantly and the flow pattern was converted from column flow to droplet flow.With the increase of ammonia dilution,the value ofCoxaincreased first and then decreased.It means that the larger contact area of the two phases could bring a better reaction effect,however,when the ammonia was diluted to a certain ratio,the decreasing reaction concentration began to have a noticeably adverse impact on the yield.In conclusion,it can be inferred that appropriate dilution of ammonia concentration is beneficial to the progress of the main reaction.We used 4 times the amount of water to dilute aqueous ammonia(25%-28%) for the next experiments.

Fig.3.Influence of the ammonia dilution on the concentration of 1-oxa-2-azaspiro[2.5] octane in the product (Coxa).Reaction conditions: -5 °C,cyclohexanone/NH3/NaClO (mole ratio)=1:1:1, w(cyclohexanone)=40%, Q(organic phase)=6.3 ml·min-1,number of microreactors in series=4.

In addition,we tested the situation that aqueous ammonia was dispersed in the organic phase and found that the reaction results were far worse than before (see the Supplementary Material for details).This result also verified that the main reaction was carried out according to the following mechanism:firstly,ammonia in the aqueous phase reacted with sodium hypochlorite to form monochloramine,and then monochloramine reacted with cyclohexanone at the phase interface.

3.2.The amount of reagents

As shown in the Fig.4,excessive sodium hypochlorite can easily cause further oxidation of monochloramine,but insufficient sodium hypochlorite is difficult to ensure the formation of high concentration of monochloramine.Therefore,the equivalents of sodium hypochlorite and ammonia need to be optimized.The microreactor can realize instantaneous mixing of multiple streams of materials,effectively avoid excessively high local concentration and improve reaction selectivity.It can be seen from Fig.5 that when the sodium hypochlorite equivalent was fixed at 1.0,the change ofCoxashowed a trend of first increasing and then decreasing with the increase of ammonia equivalent.A similar pattern was observed in the curve of sodium hypochlorite equivalent and product.Surprisingly,in both two groups of experiments,the optimal mole ratio of sodium hypochlorite and ammonia was around 2-2.5.Thus,we chose the conditions of 1.0 equivlent.ammonia and 2.0 equivlents.sodium hypochlorite for the next experiments.

Fig.4.Possible side reactions in the aqueous phase.

Fig.5.Influence of the NaClO/NH3 mole ratio on the concentration of 1-oxa-2-azaspiro [2.5] octane in the product (Coxa).Reaction conditions: -5 °C, w(cyclohexanone)=40%, Q(organic phase)=6.3 ml·min-1,number of microreactors in series=5.

Increasing the mass fraction of cyclohexanone in the organic phase can obviously boostCoxa.However,higher reactant concentration means higher requirements for heat and mass transfer.It can be seen from Fig.6 that with the increase of cyclohexanone concentration,the change ofCoxashowed a significant growth trend,but the change of reaction yield showed a trend of first increasing and then decreasing.Taken together,we considered 40%to be a preferable choice for the starting mass fraction of cyclohexanone in the organic phase.

Fig.6.Influence of the mass fraction of cyclohexanone on the concentration of 1-oxa-2-azaspiro [2.5] octane in the product (Coxa) and reaction yield.Reaction conditions: -5 °C,cyclohexanone/NH3/NaClO (mol ratio)=1:1:2, Q(organic phase)=6.3 ml·min-1,number of microreactors in series=5.

3.3.Temperature

It can be seen from Fig.7,the reaction was more suitable to be run under low temperature conditions.Although the reaction rate can be accelerated by increasing the temperature,the oxaziridine became easier to deteriorate,especially in the presence of water.Considering the potential risk of water icing in the microchannels,it was more appropriate to set the reaction temperature at -5 °C.

Fig.7.Influence of the reaction temperature on the concentration of 1-oxa-2-azaspiro [2.5] octane in the product (Coxa).Reaction conditions: cyclohexanone/NH3/NaClO (mol ratio)=1:1:2, w(cyclohexanone)=40%, Q(organic phase)=6.3 ml·min-1,number of microreactors in series=5.

3.4.Reaction time

The effect of reaction time on the reaction was also investigated.The actual reaction time could not be accurately calculated or measured due to the large amount of gas generated by the side reactions.Here we indirectly investigated the effect of reaction time on the reaction by changing the number of microreactors in series.As shown in Fig.8,the reaction time had a great influence on the reaction results,which needs to be accurately controlled.After the reaction mixture reacted in five microreactors in series,the product concentration started to drop in the following reactors,which means that the product generation rate was less than the product deterioration rate.At this time,the reaction should be terminated to ensure the reaction yield.Reaction time control on the order of seconds can be easily achieved by microreaction continuous flow,which is one of the advantages of the microreaction system for this reaction.

Fig.8.Influence of the number of microreactors in series on the concentration of 1-oxa-2-azaspiro [2.5] octane in the product (Coxa).Reaction conditions: -5 °C,cyclohexanone/NH3/NaClO (mol ratio)=1:1:2, w(cyclohexanone)=40%, Q(organic phase)=6.3 ml·min-1.

3.5.Product stability

We speculated that the low molar concentration of the product during the experiments in the batch reactor was mainly caused by local overheating,bad reaction time control,and poor two-phase mass transfer,leading to the massive deterioration of the product.Therefore,experiments were designed to examine the stability of the products in different environments (Fig.9).It was found that the product after water removal could be stably stored at low temperature for a period of time,which was consistent with the literature description [13].With the increase of temperature,the product accelerated deterioration.In the presence of water,especially alkaline aqueous solution,the product became much easier to deteriorate,after one hour the concentration dropped to the original 1% (equal volume of 0.1 mol·L-1sodium hydroxide solution,-5 °C).Therefore,the use of microreaction systems to achieve precise control of the reaction,including droplet dispersion,temperature control,reaction time control,and fast continuous phase separation,was the key to realize process intensification.

Fig.9.The stability of the 1-oxa-2-azaspiro[2.5]octane in different environments.Reaction conditions: use equal volume of water or sodium hydroxide solution.

3.6.Derivative reaction

In this section,we designed derivation experiments to evaluate the quality of the obtained high concentrations product.The reaction of 1-oxo-2-aza-snail[2.5]octane with morpholine was chosen[12] (Fig.10,detailed experimental procedures were described in the Supplementary Material).The results of the derivative reaction again verified that the effective components of the product prepared by the microreactor(1.8 mol·L-1) were several times higher than those by the batch process (0.2 mol·L-1) using the same reagent dosages in preparation of 1-oxa-2-azaspiro [2.5] octane.Moreover,high-concentration reaction reagent could reduce the dilution effect on the reaction system and had better reactivity than low-concentration reagent (Fig.10).

Fig.10.(a) The reaction scheme of derivative reaction;(b) contrast on the yield when using different Coxa of reagents.

4.Conclusions

In our work,aiming at the continuous,efficient and safe production of 1-oxa-2-azaspiro[2.5]octane by reaction of cyclohexanone with ammonia and sodium hypochlorite,a microreaction system including predispersion,reaction,and phase separation was developed.The results showed that precise control of the process including droplet dispersion,temperature control,reaction time control and fast continuous phase separation,was the key to process intensification.Under relatively optimal conditions(1.0 equivlent.NH3,2.0 equivlents.NaClO,40% (mass) organic solution of cyclohexanone,-5 °C),the concentration of 1-oxa-2-azaspiro[2.5] octane in the product could reach 2.0 mol·L-1without being concentrated under vacuum,which is much higher than that obtained in batch method (0.2-0.4 mol·L-1).Meanwhile,the results of the derivation experiments also showed that the aminating agent solution with higher concentration was more advantageous in the applications.Combined with the currently developed high-throughput micromixers and microreactors[28,29],we believe that this lab-scale microreaction system will be feasible to scale up for the industrial production of 1-oxa-2-azaspiro [2.5] octane.

Data Availability

Data will be made available on request.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

The authors gratefully acknowledge the support of the National Natural Science Foundation of China (22108264) for this work.

Supplementary Material

The supplementary material file (PDF) is available free of charge.Supplementary data to this article can be found online at https://doi.org/10.1016/j.cjche.2023.03.001.