Application of cascade unit cryogenic unit in chemical and pharmaceutical reactions

Application of cascaded cryogenic units in the production of semi-synthetic antibiotics

Semi-synthetic antibiotics are chemically or biochemically modified to change the chemical structure of known natural antibiotics, or to introduce specific functional groups to obtain a wide range of high-performance, anti-drug, small side effects, easy to use and other superior properties. Antibiotic derivatives. With the improvement of the level of medical drugs, the application of semi-synthetic antibiotics has become more widespread, which has also promoted the development of the semi-anti-industrial industry and has become one of the main development directions of the pharmaceutical industry. In the semi-synthetic antibiotic production process, some process reactions are required to be carried out in a cryogenic environment below 50 °C. In order to ensure the reaction conditions, the reaction system is often cooled to -60 ° C or even lower, and the corresponding cooling and cooling measures must be taken. At present, the commonly used deep cryogenic refrigeration methods are: liquid nitrogen evaporative refrigeration and cryogenic refrigeration. After comparing the two refrigeration methods, the cascaded cryogenic unit has its superiority in the production process of semi-synthetic antibiotics.

1 Principles of two refrigeration methods

1.1 Refrigeration principle of cascaded cryocooler

The refrigeration unit is divided into single-stage refrigeration and cascade refrigeration according to the number of refrigeration cycle stages. Single-stage refrigeration systems use a medium-temperature refrigerant. When the evaporation temperature of the refrigerant in operation is lower than -70 °C, the evaporation pressure of the refrigerant is very low, the specific volume of steam increases, the gas transmission coefficient decreases, the suction of the compressor is difficult, and the working efficiency of the unit is greatly reduced. Therefore, the single-stage refrigeration system is used. When the evaporation temperature is lower than -70 ° C, the scale is difficult to enlarge and the economy is very low.

The cascade refrigeration system consists of a high temperature part and a low temperature part. The low temperature part provides the required cryogenic capacity, and low temperature refrigerants such as R13 and R23 are used, but the condensation temperature of such refrigerants is very low, and it is difficult to condense them with cooling water under the same pressure. The high temperature portion uses a medium temperature refrigerant cycle, which functions to condense the low temperature refrigerant, and the high temperature portion and the low temperature portion share an evaporation condenser and "fold" to form a cascade refrigeration cycle using the two refrigerants.

The production process requires a reaction temperature of -50 ° C, so the cryogenic unit can fully meet the large-scale cooling requirements of the process requirements.

1.2 Liquid nitrogen evaporative cooling

Directly introducing liquid nitrogen into the reaction solution can also achieve the purpose of cooling. However, the following defects exist in the process of liquid nitrogen cooling:

1.2.1 In the process of cooling, liquid nitrogen is in direct contact with the material. The boiling point of liquid nitrogen at normal pressure is -196 °C. When the liquid nitrogen mesh distributor is sprayed, the instantaneous temperature difference is as high as 160 °C ~ -200 °C. Far from the process control temperature, resulting in a strong supercooling zone. The deviation of the local process control points must result in an unbalanced reaction process, which ultimately leads to a decline in product quality:
1.2.2 Liquid nitrogen absorbs heat and vaporizes during use. It is discharged into the atmosphere in the form of a gaseous state, and will carry some materials during the intense discharge process, thus causing a decrease in product yield and an increase in the consumption of the solvent:
1.2.3 Liquid nitrogen cooling is not easy to carry out with other materials. Because in the process of using liquid nitrogen to cool down. Due to the vaporization and expansion of liquid nitrogen, the pressure inside the reaction vessel is positive and the pressure is difficult to control. At this time, other materials must be added to participate in the reaction. The liquid nitrogen must be stopped first, which will cause the reaction temperature control to be interrupted and the process control to be biased;
1.2.4 Liquid nitrogen cannot be recycled after use, resulting in an increase in production costs;
1.2.5 The cooling process is unstable and the controllability is poor. High operational requirements. The expansion ratio of liquid nitrogen is as high as 600, and the evaporation temperature is low. In the course of use, it is easy to cause explosion due to improper operation, running materials, solidification of materials to block pipes and even personal accidents.

2 Comparison of cryogenic electromechanical and liquid nitrogen cooling

The use of cascaded cryogenic units in the semi-synthetic production process is mainly to reduce and control the temperature of the material system, to ensure that the temperature of the whole system is effectively maintained within the required range in different reaction stages, so that the drug synthesis process meets the process reaction temperature requirements. . During operation, the low-temperature refrigerant is prepared by the cascade refrigeration unit, and the refrigerant does not directly contact the reaction solution, and the reaction process is affected by indirect heat exchange, so that the refrigerant can be prevented from polluting the material. In a practical production process, the high and low temperature stages of the unit are screw type compressors with R22 and R23 as refrigerants. The evaporating temperature of the unit can reach below -80 °C, and the output is -70% to -75 °C. The capacity is up to 40,000 kcal / hour.

Through the statistical analysis of the actual production process with a scale of semi-synthetic production of 1200 tons/year, the cryogenic unit is compared with liquid nitrogen cooling:

2.1 In terms of product yield and consumption, the yield is increased by 1.88%, and the production solvent consumption is reduced by 36.1%:

2.2 In terms of quality, the product content is increased by 0.43%, which is better than liquid nitrogen cooling in terms of product stability and other impurities:

2.3 In terms of investment and power operating costs, although the one-time investment in cryogenic units and supporting cooling water installations is relatively large. Depreciation is also a factor that cannot be ignored, but the cost of purchasing liquid nitrogen is several times that of cryogenic units. Compared with the two, the cost of liquid nitrogen cooling is 5.13 times that of the cryocooler.

Through the above comparative analysis shows. In the actual production process, the cryogenic unit is compared with the traditional liquid nitrogen cooling. From product yield, solvent consumption, process control and product quality, as well as investment and power costs, it has obvious advantages, which reduces product cost and improves market competitiveness. Cryogenic unit cooling is the preferred method for building large-scale cryogenic environments.

The application of cryogenic units also takes into account other factors. For example, the refrigeration unit belongs to the rotating equipment, and its structure is relatively complicated. Therefore, the equipment operation and maintenance requirements are relatively high. In order to ensure the full advantage of the unit in production, the unit must be properly selected and scientifically maintained. In addition. The one-time investment in hardware such as equipment has increased accordingly.

3 Selection and maintenance of cascaded cryogenic units

3.1 Unit selection

Deep-cooling compressors generally include: pistons, screws, etc., and cryogenic units should be preferred to screw-type refrigeration units.

(1) There are few moving parts and it is safe and reliable to use. Since the screw compressor has no vulnerable parts such as valve plate, piston ring and crankshaft connecting rod, the structure is relatively simple, and its main moving part, the screw rotor, runs smoothly, and the trouble-free running time can reach more than 80,000 hours, so it is relatively reliable. It is more in line with the demanding requirements of reaction temperature control in the synthesis of antibiotics.

(2) Energy can be adjusted steplessly. Because the demand for cooling during the production process is dynamic. Therefore, the refrigeration unit is required to be able to perform energy adjustment efficiently. Generally, the piston compressor is gradient adjustment, that is, the adjustment of the cooling supply is realized by the unit opening and stopping mode. The frequent starting of the unit can easily cause damage to electrical and mechanical components, and at the same time, due to the large motor power, the motor Frequent start-up is easy to impact on the safe operation of the grid: the screw compressor uses a slide valve to adjust its energy level, which can achieve stepless adjustment between 10% and 100%, so it is superior to other forms in energy consumption and stability of the unit. unit.

(3) During the operation of the cascaded cryogenic unit, the high temperature partial evaporation temperature is around -30 °C, and the low temperature partial evaporation temperature is around -80 °C. During operation, there may be a part of unvaporized liquid refrigerant for piston compression. The machine is prone to liquid hammer, which causes the compressor to be scrapped in severe cases, while the screw compressor is not sensitive to a small amount of liquid.

3.2 refrigerant, brine

The refrigerant and brine of the cascade refrigeration unit are also important in the process of equipment selection. The selection of refrigerant and brine is as follows.

Refrigerant selection considerations:

(1) Security. Non-toxic, non-flammable refrigerants should be used;
(2) Economics. In the same working cycle, the COP value should be high, and the equipment operating pressure should not be too high, otherwise the operating cost of the equipment will be increased;
(3) Environmental protection. The refrigerant used should meet the commitments of the Montreal Protocol and its amendments. Refrigerants classified as eliminated should not be used, and refrigerants with good environmental performance should be preferred.

3.2.1 Medium-temperature refrigerants (R22, R407C, R410A, R404A) are generally used for high-temperature refrigerants in cascaded cryogenic units.
Through the comparison of the above various refrigerant properties, R22 has a certain superiority in economical efficiency and cycle stability, and is an excellent over-type refrigerant. So far, the State has allowed the use of HCFC-based refrigerants in the implementation of the Protocol's London amendments until 2030, so R22 should be preferred. At the same time, with the development of refrigerant technology, we must pay close attention to the development of new environmentally friendly and high-efficiency refrigerants.

3.2.2 In the cascaded cryogenic unit, the low-temperature refrigerants generally use R13 and R23. The environmental performance of R13 is relatively poor: the ODP value is 1.0, which belongs to the 10 controlled substances in the National Phase-out ODS National Plan. According to the national phase-out plan, all the R13 will be phased out on January 1, 2010. Therefore, in the selection of low-temperature refrigerants, the environmentally-friendly refrigerant R23, which can be used for a long time, should be preferred.

3.2.3 The cryogenic unit has a freezing temperature below -80 °C, so the freezing point of the selected brine must be lower than -80 °C. The commonly used brine has R11 (CFCL3 freezing point is -111.O °C), R30 ( The freezing point of CH2CL2 is -97.0 ° C). In the selection, it should be considered: R11 has poor environmental performance and belongs to the list of 10 controlled substances in the National Phase-out ODS National Plan, but the freezing point is low and the system operation is more reliable; R30 has good environmental performance, but the freezing point is high, so the unit Evaporation temperature control requirements are high, and it must be ensured that the evaporation temperature is higher than the freezing point of R30.

3.3 Cryogenic unit maintenance

The maintenance of the cryogenic unit plays a key role in the stable operation of the equipment. Therefore, a complete maintenance system must be established. The following points are introduced for this aspect:

(1) Maintenance personnel must undergo professional training, and must fully grasp the principle and performance of the equipment;
(2) The equipment should be inspected, maintained and maintained in strict accordance with the prescribed cycle, and the operation and maintenance personnel should be relatively fixed;
(3) The control components and sensing components of the equipment must be periodically verified to provide effective safety protection for the unit and to obtain objective operational raw data;
(4) The refrigerant and refrigeration oil required for the equipment should be filled according to the grades and quantities specified in the operation manual. The grades of refrigerant and refrigeration oil should not be replaced at will. The filling amount of low-temperature refrigerant should be strictly controlled. Generally, it should be 0. .lkg is a unit of measurement and must not be overfilled.

4 Practical application of domestic screw type cascade cryogenic unit

Due to the high technical requirements for the equipment, control and other components of the thermal cycle of the cryogenic unit, the cryogenic units previously used for antibiotic production mainly rely on foreign imports. With the continuous improvement of the technical level of domestic refrigeration equipment, especially for cryogenic The development of the unit has developed by leaps and bounds. The screw-type cryogenic unit designed and produced by major domestic manufacturers has won the competitive advantage in the market due to its stable operation and high cost performance. At present, this equipment has been widely used in the synthetic production process of antibiotics.

4.1 Reliability, refrigeration efficiency and equipment economy

The compressors, heat exchangers, expansion valves, measuring and control components and control systems of domestic screw-type cascade cryogenic units are all internationally renowned brand products. High-standard software and hardware provide a reliable foundation for the stable operation of the unit. The overall performance is comparable to the performance of imported equipment. The actual operation shows that under the same heat load, the cooling capacity of domestically produced units can be transported to the level of imported units to meet the production requirements; in terms of the economics of equipment investment, although the imported units and domestic units are basically the same at the hardware level, However, the purchase price is very different. Generally, the same amount of refrigeration, the same type of unit, the investment in imported equipment is more than 2.5 times that of domestic equipment. Therefore, the use of domestically produced units can reduce the upfront investment of equipment, and at the same time reduce the depreciation costs of equipment and equipment, and reduce the operating costs.

4.2 After-sales service and after-sales service, domestically produced units have obvious advantages over imported equipment, and their efficiency is higher regardless of equipment failure treatment or spare parts supply. The fault handling and technical support of imported equipment are lagging behind, and the procurement cycle of spare parts is relatively long. It is difficult to obtain timely supply of spare parts for sudden failure.

In today's highly competitive antibiotic market and low product margins, ensuring product quality and reducing manufacturing costs are prerequisites for the market. In the semi-synthetic anti-generation cable production process, as long as the correct selection of the cryogenic unit, the scientific maintenance method is adopted, which is superior to the traditional liquid nitrogen cooling method in terms of production cost, process control, product yield and product quality: Compared with imported units, domestic cryogenic units have certain advantages, especially in terms of economy. Therefore, domestic cryogenic units have a high promotion value in the production process of antibiotics.

Technical support: Zhonggong 0592-5212965/13860121165