原则：(1) 安全：化工生产中大量物质是易燃、易爆或者有毒性的。因此，设计必须充分考虑各种明显的和潜在的危险，保证生产人员的健康和安全。

(2) 操作方便：在确定各个生产过程及设备的同时，还要合理确定操作条件。因为它对生产过程与设备的确立及其作用的发挥和控制方案的确定，都有直接关系。

(3) 投资省：即要求经济地使用设备投资、土建投资、公用工程投资和人力成本。

(4) 便于安装：工厂布置应满足施工和安装作业要求。特别是应考虑大型设备的吊装，厂内道路的路面结构和载荷标准等应满足施工安装的要求。

关键词：5-氟-2,3-二氢苯并呋喃；对氟苯酚；工艺设计；反应釜

Instruction manual:

Design Project: Process design of an annual production of 30 tons 5-fluoro-2,3-dihydroisobenzofuran

Depression is a chronic mental illness with high rates of morbidity, disease burden, recurrence, disability and suicide rate. The depressive disorder is expected to the second largest human disease resulting in human death and disability by 2020, according to the latest reports of WTO. Therefore, the prevention and treatment on depression need to be attached great importance, and the studies of antidepressant should be served as a major point of pharmaceutical research. SSRIs (i.e. SSRI drugs) is an antidepressant drug widely used in clinic in recent ten years, which has characteristics of good therapeutic effect, less adverse reaction and convenient medication.However, everything has two sides, SSRIs also has shortcoming of slower action during its application in depression, especially appears more insufficiency in severe symptoms need to be relieved as soon as possible. The monoamine theory assumed that the occurrence of depression resulted from the reduction in the availability of 5-hydroxytryptamine (5-HT) and noradrenaline of the brain, which has been the main basis for designing novel antidepressant drugs.

At present, the studies about new generation of antidepressant drugs in our country are going on. The market requirement for 5-fluoro-2,3-dihydroisobenzofuran - an important intermediate of antidepressant, is showing an increasing trend. There are few reports about the batch synthesis of this intermediate in China, and the price of 5-fluoro-2,3-dihydroisobenzofuran sold in market is relatively high, which is far from to meet the requirement of market. Therefore, it is of great importance to seek for a p-propionamido- cyclohexanone synthesis route which has the following advantages of low cost, environmental protection, high yield, and is suitable for industrialized production.

As a new drug with broad prospects, extensive researches must have been conducted. There are lots of methods to synthesize 5-fluoro-2,3-dihydroisobenzofuran, but now the route for synthesis of 5-fluoro-2,3-dihydroisobenzofuran mainly has the following two kinds: (a) 4-fluorophenol was reacted with bromoacetaldehyde diethylacetal, and then the 5-fluorobenzofuran was synthesized by dehydration under the catalysis of PPA, finally, the 5-fluoro-2,3-dihydroisobenzofuran was obtained by Pd-C catalytic hydrogenation. The yield was only 31%. The production method with low yield was not suitable for scale up. The yield of dehydration step was only 45%, and the use of strong acids was not convenient for work-up and environmental protection, which was also inconsistent with the concept of green chemistry. (b) the  5-fluoro-2,3-dihydroisobenzofuran was synthesized from 4-fluorophenol by bromination to prepare 2-bromo-4-fluorophenol then reacted with dichloroethane to obtain 2-(2-bromo-4-fluoro phenoxy) chloroethane and then the intramolecular alkylation was performed through Grignard reaction. The overall yield in this production method with mild conditions was 79%, and large scale production could be feasible.

The yield in scheme a is only 31%, low yield is not suitable for mass production. The yield in dehydration step is only 45%, and the use of strong acids is not convenient for work-up and environmental protection, which is also inconsistent with the concept of green chemistry. The reaction conditions in scheme b are mild, with overall yield of 79%, which is convenient for large scale preparation. The yield and purity of the finished product are enhanced greatly, which is conducive to final purification. Large scale production of target product might be able to realize through process design.