摘要
含氟药物由于生物活性高、效果好、毒性低等受到人们普遍关注，临床应用迅速发展，成为十分抢手的强力广谱抗菌消炎药，总需求量呈较大增长趋势。所以，作为含氟类药物——氟喹诺酮类抗菌素中间体氟氯苯胺的生产中，3-氯-4-氟-硝基苯(也称2-氯-1-氟-4-硝基苯)制备工艺的优化或改进对降低含氟药物整个生产过程成本、提高产品收率和质量起到关键的作用。现有的溶剂法生产3-氯-4-氟-硝基苯工艺虽然具有技术成熟的优点，但存在溶剂用量大、回收不完全从而污染环境、反应温度高且副反应多、收率较低等问题。为消除溶剂对环境的污染，提高产品收率，本文提出一条新的合成3-氯-4-氟-硝基苯工艺路线：采用相转移催化剂(PTC)，高活性氟化剂，使3，4-二氯硝基苯(也称1,2-二氯-4-硝基苯)发生氟氯置换合成3-氯-4-氟-硝基苯。
为此，本文首先在自行设计的塔式氯化器中，以对硝基氯苯为原料，路易氏酸作催化剂，分子氯氯化合成3,4-二氯硝基苯(合成3-氯-4-氟-硝基苯的原料)，根据该氯化过程特征，利用正交试验设计方法结合单因素实验考察了有关因素对氯化过程的影响，优化得到了最佳的氯化工艺条件，3，4—二氯硝基苯的收率可达83.26％。比文献报道的最高收率高3.26个百分点。
其次，在3-氯-4-氟-硝基苯的合成过程中，提出了一种原料价格低廉、操作方便的重结晶过程，获得了高活性的KF，使用该种高活性的氟化剂，可使氟化产物3-氯-4-氟-硝基苯的收率比市售KF提高近25个百分点。
并在相转移催化剂存在下，通过正交试验优化得到了最佳的相转移催化氟化工艺条件，3-氯-4-氟硝基苯收率可达92.23％，比现行的溶剂法生产工艺提高6个百分点。
此外，本文还分别探讨了对硝基氯苯氯化反应和3，4-二氯硝基苯相转移催化氟化反应的动力学，得到：
氯化反应动力学方程：式中，[P]——对硝基氯苯的摩尔浓度，mol.dm~(-3)氯化反应在95℃～105℃范围内的平均表观活化能为69.68kJ.mol~(-1)。相转移催化氟化反应动力学方程：
郑州大学硕士学位论文
一鲤_2.75、10，陇
dt
一8765K
式中，[D]—3，4一二氛硝基苯的摩尔浓度，moL橱刁。
该反应在145℃~165℃温度范围的平均表观活化能为72.87kJ.mol一，。
综上所述，本文通过试验研究优化得到了合成3，4一二氛硝基苯和3一氛一4一氟一硝基
苯的最佳工艺条件，并分别探讨了其宏观反应动力学，为工程设计和工业化生产提供了
一定的设计参数和理论依据。
One kind of medicine bearing a fluorinated ring system has drawn wide attention and developed rapidly in clinical application, because of its biologically active, good effect and low toxicity. The total demand is increasing. So, as the former material of 2-chloro-1-fluoro-4-nailine that is intermediate of the medicine bearing a fluorinated ring, the optimization or improvement of technology for preparing 2-chloro-l-fluoro-4-nitrobenzene (FCNB) is the key to improve the yield and quality of product and reduce the cost of production. There are some problems in present industrialized production technology, such as using large amount of solvent, which is not be able to recover it completely and polluting environment, higher reaction temperature and side reactions, and etc. In order to delete the solvent's pollution to surroundings and improve the yield of product, another new synthesis route: l,2-dichloro-4-nitrobenzene (DCNB) reacted with highly active form of KF, in presence of a phase transfer catalyst (PTC), was discussed.
First, the preparation of l,2-dichloro-4-nitrobenzene, which l-chloro-4-nitrobenzene (PNCB) reacted with chlorine in a self-designed chlorinator, in presence of Lewis acid catalyst, .was investigated. By means of the Orthogonal Experiments design and single factor experiments, the influence of several reaction variables on the yield were examined and the optimum reaction conditions under the intervallic operation were obtained, the yield of l,2-diehloro-4-nitrobenzene was 83.26%. 3.26% higher than that reported by references. Moreover, the kinetics of chlorination under the defined sets of conditions was also studied.
The average apparent activation energy of this chlorination process in temperature range of 95℃-105℃ was 69.68kJ.mol-1 and the kinetics equation was:
where [P] is concentration of l-chloro-4-nitrobenzene, mol.dm"3.
Second, using a simple and inexpensive recrystallizing process, .a highly active form KF was obtained. It was observed to be considerably more efficient in preparing FCNB than the KF form sold in market. The yield of FCNB increased over the latter was about 25%.
The conversion of DCNB to FCNB, a nucleophilic aromatic substitution type reaction, at 140-160℃, with the recrystallized KF and Cetrimonium bromide(CTMAB) as catalyst was examined. The influence of several reaction variables on the yield was studied through
Orthogonal Experiments and the optimum reaction conditions of phase transfer catalysis fluorination wetfe obtained .Under these conditions, the yield of FCNB was 92.23%, 6% higher than that acquired by present technology in presence of certain solvent.
The kinetics of this phase transfer catalyzing fluorination process under a limited number of defined sets of reaction conditions was also studied. The average apparent activation energy of this process in the temperature range of 145℃-165℃ was 72.87kJ.mol-1 and the kinetics equation was:
where [D] is concentration of 1,2-dichloro-4-nitrobenzene, mol.dm-3. The results were obtained above can provide some design parameters and theoretical background for engineering design and industrialization of products.
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