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Efficient Production of Cyclopropylamine by a Continuous-flow Microreaction System Jin-Pei Huang, Yuhao Geng, Yundong Wang, and Jianhong Xu Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/acs.iecr.9b02438 • Publication Date (Web): 07 Aug 2019 Downloaded from pubs.acs.org on August 7, 2019

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Industrial & Engineering Chemistry Research

Efficient Production of Cyclopropylamine by a Continuous-flow Microreaction System AUTHOR NAMES. Jinpei Huang, Yuhao Geng, Yundong Wang, Jianhong Xu* AUTHOR ADDRESS. The State Key Laboratory of Chemical Engineering, Department of Chemical Engineering, Tsinghua University, Beijing 100084, China *Email: [email protected].

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ABSTRACT. Cyclopropylamine (CPA) is an essential intermediate in the preparation of many biologically active substances. The tradition batch method to prepare CPA is facing many problems in the step of Hofmann rearrangement, such as low production efficiency, poor stability and complex process. In this paper, a novel continuous-flow method to prepare CPA with high efficiency was developed. Taking advantages of characteristics of continuous-flow microreaction system, the simple process with one-stage reaction was successfully realized instead of original two-stage reaction in batch reactors. The yield of CPA reached up to 96% in only 4 min residence time at 90 ℃. Interestingly, with the higher feed temperature, the reaction concentration in continuous-flow approach can be even higher than that in the batch method.

KEYWORDS. cyclopropylamine, continuous synthesis, Hofmann rearrangement, one-stage reaction

INTRODUCTION Cyclopropylamine (CPA) is an important fine chemical intermediate, which is essential raw material for the production of floxacin antibiotics1, anti-HIV drug2 and chemical herbicides3. Currently, the global demand is more than 10,000 tons a year which is relatively large in pharmaceutical industry. The widely-used synthesis route for CPA is from γ-butyrolactone including transesterification, cyclization, amidation and Hofmann rearrangement4. Among them, Hofmann rearrangement of cyclopropanecarboxamide (CPCA) is the key step. Hofmann rearrangement is usually used to convert amide to corresponding amine, and it is a common organic reaction for the production of


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a large variety of important intermediates and fine chemical products5-7. In literatures, many reaction conditions has been described to achieve Hofmann rearrangement, such as Br2/NaOH8, NaClO/NaOH9, NBS/DBU10, lead tetraacetate11 and iodine(Ⅲ) species12. However, only condition of NaClO/NaOH is chosen in the large-scale preparation of CPA, because the reagents used in other conditions are much more expensive and would lead to much more severe environmental problems.

Scheme 1. Intermediates and products of the Hofmann rearrangement of CPCA

The reaction process of Hofmann rearrangement of CPCA 1 is described in Scheme 1 13-16. In the early period, there are two competitively parallel reactions involved in the consumption of CPCA, chlorination and hydrolysis. Chlorination is the main reaction, and hydrolysis is the side reaction. Subsequently, the chlorinated product 2 was converted to isocyanate 3 with the help of base. After that, isocyanate 3 will be hydrolyzed to give product CPA 4, or react with CPCA 1 and CPA 4 to form by-product 7 and 8, respectively. In addition, the residual sodium hypochlorite will react with CPA 4, which reduce the final yield. Because of these side reactions, Hofmann rearrangement of CPCA has been described as a process that requires utmost care to achieve desired yield.


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The conventional method is using batch reactors which are the most common devices in manufacturing pharmaceutical intermediates4,

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Considering the fact that CPCA is easy to

hydrolyze at alkaline condition and the reaction is strongly exothermal, the batch process involves two main reaction stages. At stage one, sodium hypochlorite and CPCA are mixed carefully at low temperature with a little sodium hydroxide existing. In detail, sodium hypochlorite solution is added at 0 ℃ to a suspension of the CPCA in water with cooling. The main reason for keeping cool is to prevent the subsequent reactions of isocyanate without sufficient sodium hydroxide, avoiding the undesired production of urea by-products. A reaction time of 1~2 h is needed for CPCA mainly converting into intermediates, and the actual reaction time usually varies at different batches. At stage two, sodium hydroxide solution or solid is added prior to raising the temperature for the following reaction, the purpose of that is to prevent the formation of by-products. The reaction solution is at 40~60 ℃ for 2~4 h. Up to this point, at which only a storage-stable aqueous solution of CPA is obtained, at least 3 h has passed. The high-purity CPA can be obtained by distillation. Although this kind of production method has a good yield, 85~95%, the flaws are obvious, such as low production efficiency, long total reaction time, poor stability, complex process and potential safety problem. Definitely, these flaws greatly increase the cost of manufacture of CPA. Flow chemistry is considered to be a versatile and complementary methodology for the preparation of valuable organic compounds, especially fine and pharmaceutical chemicals18-20. Compare to batch reactors, continuous-flow microreaction systems offer many benefits including unique control over reaction parameters, increased safety and easy scale-up21-23. Furthermore, with the assistance of micromixers, continuous-flow microreaction systems inherently have much smaller diffusion time and achieve mixing much faster than batch reactors24. Many reaction


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processes have been intensified successful in our previous work using continuous-flow microreaction systems, such as the preparation of poly(vinyl butyral)25, ε-caprolactam26 and azo dyes27. There is an industrial survey showing that about 40% of the reactions performed in fine and pharmaceutical industry are suitable for intensification through continuous-flow microreaction systems28. Continuous-flow systems provide a new choice for CPA synthesis. Several patents have already described continuous-flow processes to prepare CPA29, 30. However, these published processes chose similar reaction conditions to the batch method still having a low temperature reaction stage, which make the total residence time inevitably long. As a result, these continuous-flow methods became inefficient and impracticable. Continuous-flow microreaction system has excellent ability to control the reaction even under harsh conditions31, which can be used to realize process intensification thereby ensuring the economy and efficiency of the continuous-flow system32. In this case, the straight way to speed up reaction rate and reduce reaction time is to increase reaction temperature. However, if the temperature is high in early reaction period, it will be hard to prevent the isocyanate from further reacting. It is necessary to add sodium hydroxide from the beginning to avoid the formation of by-products. Therefore, for a continuous-flow method, all of the reagents are added simultaneously into reaction without the need for multiple feeds, which makes the process much simpler. As for the problem of hydrolysis of CPCA, chlorination and hydrolysis are parallel reactions, so the selectivity can be improved by regulating reaction temperature. Fortunately, we found that the activation energy of chlorination is higher than that of hydrolysis, which means that increasing the temperature helps to reduce the hydrolysis of CPCA.


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Herein, we report a new continuous-flow microreaction system to prepare CPA in order to realize process intensification. Combining original two-stage reaction into one-stage reaction, this continuous-flow system involves much simpler operation and shorter processing. By raising reaction temperature, reaction rates are accelerated by orders of magnitude and reaction times shrink from hours to minutes. More importantly, our results indicate that a high yield of CPA can be obtain easily under optimum conditions. EXPERIMENTAL SECTION Materials. Sodium hydroxide (AR, 96%) was purchased from Xilong Scientific Co., Ltd. Sodium hypochlorite (6~14% active chlorine basis) and CPCA (98%) were purchased from Aladdin (Shanghai). Sodium sulfite (98%) was purchased from Strem Chemicals, Inc. Deionized water was obtained by a Center 120FV-S water purification device. Experimental setup. The continuous-flow microreactor system consisted of a micro-mixer, a delay loop and a distillation unit as shown in Scheme 2. CPCA was dissolved in deionized water at room temperature (25 ℃) as solution A. Sodium hydroxide was added into sodium hypochlorite solution with cooling (10 ℃) and then the solution was kept at room temperature as solution B. Then, these two solutions were delivered to the system respectively by metering pumps (Beijing Xingda Science and Technology Development Co., Ltd), whose chambers were made of hastelloy instead of stainless 316 to resist corrosion of bleach. Here, we used a simple T-shaped micromixer (the inner diameter of 0.5 mm) to combine two solutions. The PTFE delay loop with an inner diameter of 1.8 mm and an external diameter of 3 mm was connected directly downstream to the micromixer, and it was submerged in the water bath to control the temperature concisely. The residence time can be regulated by changing the length of the delay loop and the total flow rate. A


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quench unit was designed at the outlet of delay loop to stop the reaction, and sodium sulfite (0.5 mol/L) solution was used as quencher. The reaction mixture finally flowed into a distillation unit to distilling the product from the mixture. Using a simple distillation flask, the main portion of CPA with relatively high purity (~95%) was obtained at a head temperature of 49 ℃, while another aqueous CPA solution containing more than 20% of the theoretical yield of CPA was obtained in the range from 50 ℃~ 99 ℃. Better separation results can be achieved by rectification column. In this case, we were much more concerned about the reaction than separation. So, for convenience, we used simple distillation device and collected the distillate of 49 ℃~ 99 ℃ to determine the reaction yield. The distillate was then analyzed by GC with FID detector, and the concentration of CPA was determined by internal standard method (see Supporting Information for details).

Scheme 2. Schematic of the continuous-flow reactor system While in the early stage of experiment, a relative long reaction time (>10 min) was needed for studying reaction kinetics and exploring suitable reaction conditions. Although we can regulate the reaction time by changing the length of the delay loop and the total flow rate in a continuousflow system, it is not time-efficient and economical at all when reaction time is too long. So we chose to use a “stop-flow” microtubing (SFMT) parallel reactor system instead of a continuousflow microreaction system in the early stage. SFMT system is an efficient and effective platform for reaction screening whose design is derived from continuous-flow microreaction systems with the addition of batch elements. Instead of flowing the reaction mixture continuously, SFMT system


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allows the flow to be paused at will. The SFMT system is based on a “switch in and out” approach through the use of two shut-off valves at each end of the micro-tubing reactor (Scheme 3). Once the micro-tubing reactor is filled with reactor mixture, both of the valves are closed, and the sealed reactor coil is disconnected from the system. The filled reactors are then placed into the water bath until the desired reaction time has been achieved. The other parts of the SFMT system are the same as the continuous-flow system. More introduction about SFMT parallel reactor can be found in Wu’s work33. Through experiments we found the deviation of the results between these two systems is within 1% when residence time is more than 5 min.

Scheme 3. Schematic of the SFMT system

RESULTS AND DISCUSSIONS Parallel reactions. Firstly, the hydrolysis of CPCA was studied. We used deionized water to replace sodium hypochlorite in Solution B, and studied the situations adding or not adding NaOH. The concentration of CPCA in reaction mixture can be directly determined by HPLC. The results


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show that CPCA has high stability under neutral condition (Figure 1). At 90℃, there is little decomposition (< 0.5%) of CPCA in 10 minutes. But under strong alkaline condition, it appeared significant hydrolysis, especially at high temperature. Under two equivalents of alkali, more than 30% of CPCA decomposed when kept at 90 ℃ for 10min. Therefore, when ready to add the base from the beginning, we should take into consideration the hydrolysis of the CPCA.

Figure 1. The hydrolysis of CPCA. The initial concentration of reactants in the mixture, CPCA: 0.59 mol/L, sodium hydroxide: 1.18 mol/L (black), 0 mol/L (blue).

Figure 2. The chlorination of CPCA. The initial concentration of reactants in the mixture, CPCA: 0.59 mol/L, sodium hydroxide: 1.18 mol/L, sodium hypochlorite: 0.59 mol/L. The data of 15 min, 20 min and 25 min was obtained by SFMT system.


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For another reaction, chlorination, the reaction rate cannot be calculated by the change of concentration of CPCA due to exist of hydrolysis. Unlike the commonly purchased sodium hypochlorite solution, which starts to dramatically decompose at more than 70 ℃, sodium hypochlorite with high concentration of sodium hydroxide has good stability even at 90 ℃ (Figure S7). Therefore, the effect of self-decomposition can be ignored. It is reasonable to characterize the rate of chlorination with the reduction of concentration of sodium hypochlorite in this case. And the concentration of sodium hypochlorite in the mixture can be determined by iodometry (see Supporting Information for details). As can be seen from the Figure 2, the chlorination rate also increases rapidly with increasing temperature, but the influence of temperature on chlorination seems much larger than hydrolysis. Assuming that the reaction rates of hydrolysis and chlorination of CPCA follow rate Equation 1 and 2 respectively, the activation energies of these two reactions can be obtained by fitting the experimental data to Arrhenius formula (see Supporting Information for details). The results show that the ration of activation energy of chlorination to hydrolysis is about 2, which means increasing temperature is beneficial to improving the selectivity of chlorination, the main reaction. In another word, raising the temperature doesn’t mean more hydrolysis, which is good for continuous-flow reaction process. Equation 1. v1  k1c(CAPA)c( NaOH ) Equation 2. v2  k2 c(CAPA)c( NaClO) Mixing. If the two solution are mixed unevenly, for CPCA, there will be in some places high local concentrations of NaClO and NaOH, while in some places low local concentrations of NaClO


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and NaOH. Due to one-step reaction, high local concentrations of NaClO will cause serious further oxidation of CPA. And low local concentrations of NaOH will lead to large formation of urea byproducts. So efficient mixing is significant for this process that we need micromixer to ensure uniformity of the reaction mixture. For micromixers, the mixing efficiency is not only related to the microstructure, but also related to the flow velocity. With the flow velocity increasing, the mixing between two solutions becomes more violent in the micromixer. It will improve the mass transfer and shorten the time required for complete mixing. Therefore, the influence of mixing efficiency on the reaction result can be tested by changing the flow velocity. Throughout the experiments, other parameters such as residence time, temperature and flow rate ratio remained constant. As can be seen from the Figure 3, a plateau appeared when total flow velocity in micromixer reached 7.5 m/s, which indicates that the mixing efficiency is good enough and will not affect the mixing and product yield anymore.

Figure 3. Yield of CPA with different total flow velocities in micromixer. The initial concentration of reactants in the mixture, CPCA: 0.59 mol/L, sodium hydroxide: 1.30 mol/L, sodium hypochlorite: 0.65 mol/L; flow ratio: solution A/solution B=0.5; reaction temperature: 90 ℃; the residence time: 10 min. Temperature. Next, we turned our attention to the influence of the reaction temperature. As shown in Figure 4, with the increase of reaction temperature, the reaction rate is accelerated rapidly.


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The required residence time was shortened from more than 1 hour at 50 ℃ to 4 min at 90 ℃. As for the yield of CPA, it also has a slight improvement with the increasing reaction temperature. As distillation unit is a high temperature zone, what happens if reaction mixture flows directly into the distillation unit without any stay in the delay loop? First of all, the reaction will become difficult to control, and one of the greatest advantages of continuous-flow system is lost. Secondly, there will be a serious back mixing phenomenon in the reaction process. Because the CPA may have side reactions with intermediate, isocyanate, the yield will be reduced by 3~4% in our cases.

Figure 4. The influence of the temperature on reaction rate. (a) 50 ℃, 60 ℃ and 70 ℃ (data was obtained by SFMT system); (b) 80 ℃ and 90 ℃. The initial concentration of reactants in the mixture, CPCA: 0.59 mol/L, sodium hydroxide: 1.30 mol/L, sodium hypochlorite: 0.60 mol/L. Optimization of the amount of reagents. The excess sodium hypochlorite will continue to react with the product to produce oxidation by-products that reduces the final yield. Since sodium


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hypochlorite is not easy to decompose, the equivalent ratio of sodium hypochlorite (based on CPCA) close to 1 would be more appropriate. Considering that the amount of sodium hypochlorite will also affect the time required for complete reaction, 1.02-1.04 is better, as shown in Figure 5.

Figure 5. Yield of CPA with different equivalents of NaClO. The initial concentration of reactants in the mixture, CPCA: 0.59 mol/L, sodium hydroxide: 1.30 mol/L; reaction temperature: 90 ℃, residence time: 5 min.

Figure 6. Yield of CPA with different equivalents of NaOH. The initial concentration of reactants in the mixture, CPCA: 0.59 mol/L, sodium hypochlorite: 0.65 mol/L; reaction temperature: 90 ℃, residence time: 5 min. With the increase of sodium hydroxide, the yield increases (as shown in Figure 6), which indicates that at high temperature, the formation of dicyclopropylurea is the main side reaction, not the hydrolysis of CPA. And when the equivalents of sodium hydroxide reach 2.1, the increase


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become much slower. 2.1-2.2 equivalents of sodium hydroxide would be an ideal condition for economy and treatment of wastewater. Feed temperature. One more thing to consider is the solubility of CPCA. The CPCA has a low solubility in water at low temperature (2 ℃, 6 wt.%; 25 ℃, 17 wt.%). In batch reactors, suspending liquid of CPCA can be used to increase the reaction concentration (17~22 wt.%). It may have a negative impact on yield, but it won’t cause lots of problems. However, for continuous-flow reaction process, there will be many problems when using suspension feed, such as channel blockage and uniformity of mixture concentration. In US patent 5,728,87334, the suspension of cyclopropanamide was mixed with sodium hypochlorite and sodium hydroxide solution in a batch reactor at a low temperature first to obtain a homogeneous solution. And then, the homogeneous solution flowed into a tubular reactor of high temperature for continuing reaction. In this method, pre-reaction in batch reactor was used to avoid suspension feed in tubular reactor, but it made the process more complicated and less efficient. In order to ensure the concentration of the reaction solution and productivity, higher feed temperature was utilized in continuous-flow reaction. Previous experiments showed that CPCA is stable under neutral conditions, so higher feed temperature is feasible. The only thing needed to pay attention is the heat preservation of the feed section of solution A. We have tested 22 wt.% solution A of 40 ℃ successfully in continuous-flow microreation system, and got 96% yield under optimal condition (1.02eq sodium hypochlorite, 2.2eq sodium hydroxide, 90 ℃ and 4 min), corresponding to the production of 42 g/h (total flow rate of 15mL/min). CONCLUSION


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In summary, we have developed an efficient continuous-flow microreaction system to produce CPA with only one stage reaction. Excess reagents are very few: about 2% of excess of sodium hypochlorite and 10% of excess of sodium hydroxide based on stoichiometric ratio, while in traditional method the values were around 5% and 10%, respectively. Meanwhile, only a residence time of 4 min in delay loop at 90 ℃ was employed to produce CPA in 95~96% yield with high stability compared to over 3 h to generate an unstable yield (85~95%) in traditional batch reactor. Higher feed temperature of 40 ℃ was used to increase reaction concentration due to the low solubility of CPCA at low temperature. Combined with the current existing high-throughput micromixers21, 23, this simple continuous-flow system will be very easy to scale up, which shows great potential in real applications of continuous-flow microreaction technology. ASSOCIATED CONTENT Supporting Information. The following file is available free of charge. GC analysis method of cyclopropylamine, estimation of activation energies of hydrolysis and chlorination of CPCA, determination of concentration of sodium hypochlorite in the mixture by iodometry, and the stability of sodium hypochlorite with high concentration of sodium hydroxide. (PDF)

AUTHOR INFORMATION Corresponding Author *Email: [email protected]. Notes The authors declare no competing financial interest.


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ACKNOWLEDGMENTS The authors gratefully acknowledge the supports of the National Natural Science Foundation of China (21636004, 21476121) for this work.


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