A novel nitration process was developed for the production of 4-(4-methoxy-3-nitrophenyl)morpholine. Crude 4-(4-methoxyphenyl)morpholine produced in step 1 was converted to its nitric acid salt. The nitration reaction was carried out by adding a dichloromethane solution of the isolated salt to concentrated sulfuric acid. This protocol provided an easy and reliable way to obtain a 1:1 molar ratio of the substrate and nitric acid in the reaction mixture and was proven to be the most effective method to prevent under-/over-nitration. The incorporation of the protocol into the process resulted in substantial improvement of the robustness and safety profile of the whole process. In addition, 59% overall yield improvement, 30% capacity increase, 40% waste reduction, and simplified operations were achieved. A detailed thermal hazard analysis of the process was also performed.

中文翻译：

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一种新颖，安全，稳定的硝化过程，用于合成4-（4-甲氧基-3-硝基苯基）吗啉

开发了一种新的硝化方法以生产4-（4-甲氧基-3-硝基苯基）吗啉。将步骤1中产生的粗4-（4-甲氧基苯基）吗啉转化为其硝酸盐。通过将分离的盐的二氯甲烷溶液加入浓硫酸中进行硝化反应。该方案为获得反应混合物中底物和硝酸的摩尔比为1：1的方法提供了一种简单可靠的方法，并且被证明是防止硝化不足/硝化过度的最有效方法。将协议合并到过程中，可以显着改善整个过程的健壮性和安全性。此外，总体产量提高了59％，产能提高了30％，废物减少了40％，并且简化了操作。