微通道反应器具有独特的内部结构能够改善流体的混合、增强传质和传热，适用于多相反应以及高风险或恶劣条件下的反应高温低温等条件。缩短反应时间，减少溶剂浪费，提高选择性，提高产量和产品纯度，消除安全风险，减少环境污染，实现从实验室到无缝放大工业生产。

Microchannel reactor has a unique internal structure that can improve fluid mixing, enhance mass and heat transfer, and is suitable for multi-phase reactions and high temperature and low temperature reactions under high risk or harsh conditions. Shorten reaction time, reduce solvent waste, improve selectivity, increase yield and product purity, eliminate safety risks, reduce environmental pollution, and achieve seamless scale-up from the laboratory to industrial production.

  由于连续流微通道反应器能达到的温度更高，化学反应速率则更高。连续流微通道反应器耐压高达20bar，耐温可达100-150°C。通过阿伦尼乌斯公式(Arrhenius equation )可知，每升高10°C，反应速度就会加快2倍，连续流微通道反应器可以大幅度提高反应速度。

  连续流动反应比间歇反应更安全，因为在反应的任何阶段，只有极其微量的反应物或危险性物质在反应。反应器微流控芯片将化学反应集中在一个小芯片上进行反应。相比于传统间歇式反应器一次性混合的作业方式，微流控芯片更加安全可靠。例如一个10升的间歇式反应釜发生爆炸，后果可能是致命的。然而10升的物料可以通过10毫升微通道反应器连续的反应，确保在任何时候都只有10毫升物料在反应。在间歇式反应釜中一分钟进行的反应，在连续流反应器中可连续运行一夜。

  Since the continuous flow microchannel reactor is able to reach higher temperatures, the chemical reaction rate will increase accordingly. The reactor can withstand pressure up to 20bar and temperature up to 100-150°C. According to Arrhenius equation, the reaction rate will increase by 2 times for every 10 degree C increase, so the reactor can significantly improve the reaction rate.

  Continuous flow reaction is safer than batch reaction, because only a very small number of reactants or hazardous substances are involved at any stage of the reaction. The microfluidic chip on the reactor concentrates the chemical reaction on a small chip. Compared with the one-time mixing method used in traditional batch reactors, microfluidic chips are safer and more reliable For example, if a 10 liter batch reactor explodes, the consequences are likely to be fatal. But 10 liters of material can undergo continuous reaction through a 10 milliliter microchannel reactor, ensuring that only 10 milliliters of material are in a reaction state at any time. This greatly reduces the risk of reaction. A reaction that takes one minute in an intermittent reactor can run continuously overnight in a continuous flow reactor.

图1 连续流化学反应器

Fig. 1 Continuous Flow Microchannel Reactor

图2 连续流化学反应系统

Fig. 2 Continuous flow chemical reaction system

图3 连续流合成三唑的合成工艺图

Fig. 3 synthesis process of triazole by continuous flow synthesis

图3为连续流合成三唑的合成工艺图。在本例中，连续流反应的风险为间歇式反应风险的千分之一。危险性分析：三唑属于叠氮化物，禁止中、大规模使用。β-叠氮乙基苯基硫化物；沸点65℃。由于原料涉及爆炸性试剂叠氮乙基，所以通过间歇式反应釜合成三唑的工艺过程，存在产率低、区域异构体和重大安全隐患。可以选用热稳定性更好的β-叠氮乙基苯基硫化物作为叠氮乙基替代物，在连续流反应器中进行反应。在流动中进行反应进一步提高了安全性，限制了反应工艺过程中形成/反应的叠氮化物的数量，显著提高了收率。

The figure 3 shows the synthesis process of triazole by continuous flow synthesis. In this case, the risk of a continuous flow reaction is one-thousandth that of a batch reaction. Risk analysis: Triazole belongs to azide, it is prohibited to use in medium and large scale. β- Azide ethyl phenyl sulfide: boiling point 65 ℃. Because of the explosive properties of ethyl azide, the synthesis of triazole by batch reactor has some problems such as low yield, regional isomer and major safety risks. The ethyl azide can be replaced with a more thermally stable β-ethyl azide phenyl sulfide. The reaction is carried out in a continuous flow reactor. By limiting the amount of azides formed/reacted at each time, reacting in a flow manner improves safety and significantly increases yield.

图4 连续流反应器合成Hantzsch噻唑和后续脱氢化流程

FIG. 4 Synthesis of Hantzsch thiazole in continuous flow reactor and subsequent dehydrogenation process

流动化学备受关注的主要原因之一是它使得反应速度更快产量更高，可大幅度节省时间。通过改变总流量来改变反应时间，改变进料流体流量比例来改变试剂比例，改变溶剂流量来改变物料浓度。不同于需要清洗后重新开始按设定的反应条件进行的间歇式反应釜，连续流反应器总容量仅10毫升。溶剂流经过通道后即可开始下一个反应条件。使用者仅需15分钟的准备时间就可以研究50-100种反应条件。

快速优化噻唑合成的一个例子如图4，斯坦福-伯纳姆医学研究所(SBMRI)的研究人员通过连续流反应器对Hantzsch噻唑合成和后续脱氢化流程进行优化。通过改变停留时间、反应温度和水当量，用户通过9次实验就确定了Hantzsch噻唑合成的最佳反应条件，总实验时间仅为37.5分钟。

One of the main reasons flow chemistry is getting a lot of attention is its ability to greatly save time by speeding up reactions and increasing yields. The user can change the reaction time by changing the total flow rate, change the reagent ratio by changing the feed fluid flow rate, and change the solvent flow rate to change the material concentration. Unlike the batch reactor that needs to be cleaned and restarted according to the set reaction conditions, the total capacity of the continuous flow reactor is only 10 ml. After the solvent flow passes through the channel, the next reaction can be started Users can study 50-100 reaction conditions with just 15 minutes of preparation time.

An example of rapid optimization of thiazole synthesis. (Figure 4). Researchers at the Stanford-Burnham Medical Research Institute (SBMRI) optimized the Hantzsch thiazole synthesis and subsequent dehydrogenation process via continuous flow reactor. The user performed 9 experiments by varying the residence time, reaction temperature and water equivalent to finally determine the optimal reaction conditions for the synthesis of Hantzsch thiazole. The total experimental time was only 37.5 minutes.

图5 5-(噻唑-2-基)-3,4-二氢嘧啶-2(1H)- 1的多步连续流合成案例

FIG. 5 Multistep continuous flow synthesis of 5-(thiazol-2-yl)-3, 4-dihydropyrimidine-2 (1H) -1

高通量化学(或化合物库合成)应用平行操作过程，以大通量进行合成/制备、分析和活性筛选的化学。例如组合化学。高通量化学主要应用于药物发现和开发化学，可以快速识别先导化合物。传统的批处理方式是通过在多个小烧瓶和小瓶中进行反应，例如Atlas Orbit系统。然而，通过微通道反应器对反应过程使用自动化试剂添加和产品收集模块，可以实现每天10 - 100种化合物的快速、连续高通量合成和纯化。

斯坦福-伯纳姆医学研究所(SBMRI)的研究人员使用连续流微通道反应器对5-(噻唑-2-基)-3,4-二氢嘧啶-2(1H)- 1的多步连续流动合成进行优化。（如图5）研究人员发现，连续的Hantzsch噻唑合成、去酮化和Biginelli多组分反应可以快速有效地获得高度功能化且具有药理意义的5-(噻唑-2-基)-3,4-二氢嘧啶-2(1H)- 1，而无需分离中间体。仅经过三个连续的反应，在15分钟内即可合成得到这些复杂的小分子，且收率高达39-46%。

High throughput chemistry (or compound library synthesis) is chemistry that applies parallel operating processes for synthesis/preparation, analysis, and activity screening at large throughput. For example, combinatorial chemistry. High throughput chemistry is primarily used in drug discovery and development chemistry, where lead compounds can be quickly identified. Traditional batch processing is done by reacting in multiple small flasks and vials, such as the Atlas Orbit system. However, rapid and sequential high-throughput synthesis and purification of 10-100 compounds per day can be achieved using automated reagent addition and product collection modules for the reaction process via microchannel reactors.

Researchers at the Stanford-Burnham Medical Institute (SBMRI) used a continuous-flow microchannel reactor to optimize the multi-step continuous-flow synthesis of 5-(thiazol-2-yl)-3,4-dihydropyrimidine-2(1H)-1. (Figure 5)  The researchers found that successive Hantzsch thiazole synthesis, deketoation, and Biginelli multi-component reactions can quickly and efficiently obtain highly functional and pharmacologically significant 5-(thiazol-2-yl)-3,4-dihydropyrimidine-2(1H)-1 without the need to separate intermediates. After only three consecutive reactions, these complex small molecules can be synthesized in less than 15 minutes with yields of up to 39-46%.

图6 连续流反应器多步合成DHPMs

FIG. 6 Multistep synthesis of DHPMs in continuous flow reactor

连续流反应器可快速多步合成各种复杂的药物化合物。各步骤快速反应优化。原位生成HBr会破坏酮体的保护作用，促进多组分反应。图6所示收率为单个反应的收率。

连续流反应能达到传统间歇式反应釜无法达到的反应条件。主要包括2个原因，连续流反应的混合是通过流体扩散进行反应的，相较于传统的间歇化学反应，其速率更快，效率更高。可以在反应前对连续流反应器进行预热或预冷，意味着物料在其内部反应几乎可以瞬间达到反应温度，而传统的间歇化学反应中，需要一边对整个反应釜内的物料进行搅拌一边对其进行加热或冷却，其升温或降温时间更长，容易发生过热或过冷反应。例如，用户可以在低温下使反应物去质子化，然后加入亲核试剂并立即加热到高温。连续流反应器能够在更高的压力和温度下工作，甚至高于溶剂的沸点，可以创造全新的杂环支架。

The continuous flow reactor can quickly synthesize various complex drug compounds in multiple steps. Rapid response optimization of each step. In situ formation of HBr will destroy the protective effect of ketone bodies and promote the multi-component reaction. The yield shown in Figure 6 is the yield of a single reaction.

The continuous flow reactor can quickly synthesize various complex drug compounds in multiple steps. The continuous flow reaction can achieve the reaction conditions that the traditional batch reactor cannot achieve. There are two main reasons: the mixing of continuous flow reactions is carried out by fluid diffusion, which is faster and more efficient than traditional intermittent chemical reactions. The continuous flow reactor can be preheated or pre-cooled before the reaction, which means that the material can reach the reaction temperature almost instantaneously in its internal reaction, while the traditional intermittent chemical reaction, the need to stir the material in the entire reactor while heating or cooling. In this way, it takes longer to heat up or cool down, and it is prone to overheating or subcooling reactions. For example, the user can deprotonate the reactants at low temperatures, then add nucleophiles and immediately heat to high temperatures. Continuous flow reactors are capable of operating at higher pressures and temperatures, even higher than the boiling point of solvents, allows for the creation of entirely new heterocyclic scaffolds.

图7 吡唑硝化反应流程图

FIG. 7 Flowchart of pyrazole nitration reaction

图8间歇式反应器与微反应器的温度变化情况及其对副产物产生的影响

FIG. 8 Temperature variation in batch reactor and microreactor and its effect on by-product production

图7和图8为使用连续流反应器开发简单、快速、安全的硝化和溴化反应工艺。由于温度、浓度和进料/搅拌速率不同，传统间歇式反应釜的普遍存在选择性低的问题。连续流反应器可以实现更好控制反应，提高产物收率。连续流反应器由于其通道尺寸微小，体积比和扩散混合使得其表面积更高，其选择性更好。与夹套反应釜（其内部存在较大的温度梯度）的加热方式相比，连续流反应器的温控效果更好。在危险化学品工艺中，连续流反应器避免了潜在危险中间体的积累，将事故的风险降到最低。

Figures 7 and 8 show the development of a simple, fast, and safe nitrification and bromination reaction process using a continuous flow reactor. Due to differences in temperature, concentration and feed/mixing rate, low selectivity is common in traditional batch reactors. The continuous flow reactor can better control the reaction and increase the product yield. Continuous flow reactor has better selectivity due to its small channel size, higher surface area due to volume ratio and diffusion mixing. Compared with the jacketed reactor (which has a large temperature gradient inside), the continuous flow reactor has better temperature control effect. In hazardous chemical processes, continuous flow reactors avoid the accumulation of potentially hazardous intermediates and minimize the risk of accidents.

图9传统间歇式反应釜中CaCl₂与Na₂CO₃反应合成CaCO₃

FIG. 9 Reaction of CaCl₂ and Na₂CO₃ to synthesize CaCO₃ in traditional batch

图10连续流反应器中CaCl₂与Na₂CO₃反应合成CaCO₃

FIG. 10 Reaction of CaCl₂ and Na₂CO₃ to synthesize CaCO₃ in continuous flow

图9为传统间歇式反应釜中CaCl2与Na₂CO₃反应合成CaCO₃。图10为连续流反应器中CaCl2与Na₂CO₃反应合成CaCO₃。

FIG. 9 shows the CaCO₃ synthesized by CaCl2 and Na₂CO₃ in a traditional intermittent reactor. FIG. 10 shows the CaCO₃ synthesized by the reaction of CaCl2 and Na₂CO₃ in a continuous flow reactor.

实验者在两个实验中使用完全相同的浓度、温度和反应/停留时间。根据连续流动化学技术的原理，相较于传统间歇式反应釜，其在工艺放大过程会容易得多。通常来说，从实验室规模的小试实验扩大到工艺规模的中试放大实验，可能导致非常严重的放热失控，因此需要反应量热法。

对于连续流动，如果你想要10-100倍的规模，可以简单地增加反映的停留时间即可实现产量扩大。

The experimenter used exactly the same concentration, temperature, and reaction/residence time in both experiments. According to the principle of continuous flow chemistry technology, it is much easier to scale up the process than the traditional batch reactor. In general, scaling up from small laboratory scale experiments to pilot scale experiments on a process scale can lead to very serious runaway heat release, so reaction calorimetry is required.

For continuous flow, if you want 10-100x scale, you can simply increase the residence time of the reflection to achieve increased production.

图11连续流中亲核取代反应的放大

FIG. 11 Scale-up of nucleophilic substitution in continuous flow

连续流反应器容积为16ml，进料流速为2.5毫升/分钟，停留时间为3.2分钟。反应温度为150摄氏度，二氧六环在标准大气压下的沸点是100摄氏度，图11为得到的50g产品。

FIG. 11 shows the amplification of the nucleophilic substitution reaction in a continuous flow. The volume of the continuous flow reactor is 16ml, the feed flow rate is 2.5 ml/min, and the residence time is 3.2 minutes. The reaction temperature is 150 degrees Celsius, and the boiling point of dioxane at standard atmospheric pressure is 100 degrees Celsius. The FIG. 11 shows the resulting 50g product.、

图12为连续流反应器内后处理示意图

FIG. 12 The schematic diagram of reprocessing in the continuous flow reactor

图13固相试剂/清除剂/过滤图

Figure 13 the solid phase reagent/scavenger/filtration diagram

在传统的间歇化学中，分析多个反应可能需要多个探测点（每个反应器一个）。然而，在连续流化学中，许多不同的反应可以在同一个探针下“流动”，因为反应是流动的，所以反应会自动转移到分析系统。流动化学系统可以设计采样和稀释模块，可自动微量取样并分析。

操作步骤如下；从反应器中提取5微升样品，稀释（稀释倍数5-250）后注入色谱系统。稀释可避免色谱检测器出现满刻度偏转问题。可实现反应中间取样或用户设定规定间隔取样（作为生产运行中的质量控制）。

传统的间歇反应釜一般需要单独的后处理来进行，例如水性后处理、过滤或固相清除。在连续流化学中（如图12和图13所示），流动的物料已经可以实现液-液萃取和固相试剂/清除剂/过滤的在线（集成）处理。

剑桥大学的研究人员通过连续流反应器多步合成氧代马里替丁。通过均相和非均相反应(包括气相)的混合，在流动条件下进行合成、蒸馏和后处理，氧代马里替丁的收率高达40%。

In conventional batch chemistry, analyzing multiple reactions may require multiple probe points (one per reactor). However, in continuous flow chemistry, many different reactions can "flow" under the same probe, and because the reaction is flowing, the reaction is automatically transferred to the analytical system. Flow chemistry systems can be designed with sampling and dilution modules to automatically micro-sample and analyze.

The procedure is as follows; 5 microliters of samples were extracted from the reactor, diluted (dilution factor 5-250) and injected into the chromatographic system. Dilution avoids the problem of full scale deflection in chromatographic detectors. Sampling in the middle of the reaction or at specified intervals set by the user (as quality control in the production run) can be achieved.

Conventional batch reactors generally require separate post-treatment, such as water-based post-treatment, filtration or solid removal. In continuous flow chemistry(As shown in Figures 12 and 13), the flowing material can already be handled in line (integrated) with liquid-liquid extraction and solid phase reagents/scavengers/filtration.    

Researchers at the University of Cambridge synthesized oxymaritidine in multiple steps in a continuous flow reactor. Through the mixture of homogeneous and heterogeneous phase reactions (including gas phase), synthesis, distillation and post-treatment under flow conditions, the yield of oxymaritidine is up to 40%.

图14 3-羟甲基吲哚的合成和加工实例

FIG. 14 Examples of synthesis and processing of 3-hydroxymethylindole

如图14所示。Shea等人通过连续流微反应器合成3-羟甲基吲哚的工艺流程。反应器对每个反应的连续液-液萃取进行后处理。这些吲哚以烯丙基三甲基硅烷和甲醇作为亲核试剂来实现酸催化的亲核取代。总的来说，一组4个3-羟甲基吲哚通过一系列转化转化为36个吲哚衍生物，包括碘镁交换/亲电捕获和酸催化的亲核取代，以全自动顺序方式进行。

       As shown in Figure 14. Shea et al. demonstrated an automated sequential approach for the generation and reactions of 3‐hydroxymethylindoles in continuous‐flow microreactors. The synthetic flow strategy could be coupled with an in line continuous liquid–liquid extraction workup protocol for each reaction. Further elaboration of each of these indoles within the fluidic setup was achieved by acid‐catalysed nucleophilic substitutions with allyltrimethylsilane and methanol used as nucleophiles. Overall, a set of four 3‐iodoindoles was converted into thirty‐six indole derivatives by a range of transformations including iodo–magnesium exchange/electrophile trapping and acid‐catalysed nucleophilic substitution in a fully automated sequential fashion.