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Improvement of Production process for pharmaceutical intermediates Guanidine hydrochloride|50-01-1|

2014-12-31 来源:亚科官网
Abstract: This article provides a guanidine hydrochloride production process with simple production process, easy control of reaction process, and high product purity. It solves the problems existing in the existing technology, obtains considerable economic benefits, and also solves environmental problems.
Keywords: Guanidine hydrochloride; process improvement; melt reaction;
Guanidine hydrochloride, chemical name carbamate hydrochloride, its structural formula: HN=C(NH2)2HCl, molecular formula: CH6ClN3. White or light yellow lumps, melting point 181-183°C, relative density 1.354, 25°C, 4% aqueous solution pH=6.4, solubility in 100g of the following solutions at 20°C: 200g/100g water, 76g/100g methanol, 24g/100g ethanol, almost insoluble in acetone, benzene and ether. It can be used as pharmaceuticals, pesticides, dyes and other organic synthesis intermediates, is the important raw material for the production of sulfadiazine, sulfamethazine, sulfamethazine and other drugs and folic acid, it can also be used as synthetic fiber antistatic agent.
At present, dicyandiamide and ammonium salt (ammonium chloride) are generally used as raw materials, and the melting reaction is performed at 170-230°C. Ammonia gas is introduced into the reaction system as an auxiliary agent during the reaction to increase the crude product yield and purity. After the reaction is completed, the solid guanidine hydrochloride is obtained after being sliced by a slicer, and refined to obtain a final product. The process uses ammonia as a reaction aid. On the one hand, liquid ammonia storage tanks and other related equipment are needed, which increases unsafe factors and increases production costs. On the other hand, ammonia reacts with dicyandiamide and ammonium chloride during the melting reaction process. Melamine, melamine-amide and melamine diamide and other impurities are easy to produce becaue of severe exothermic heat, affect the purity of the product, increase refining costs.
In order to solve this kind of problem, this article has developed a kind of production craft that the production craft is simple, the reaction process is easy to control, the product purity is high.
1 synthesis method
1680g of dicyandiamide, 2030g of ammonium chloride, and 297g of ammonium carbonate were mixed together and slowly added while stirring, and the mixture was heated to 200°C. The solids in the reactor were all dissolved. The reaction temperature was controlled at 200-210°C for 2.5 hours. The crude guanidine hydrochloride was put to about 3858g, the crude product content was 95.6%, and the free ammonium content was measured.
Refining: At room temperature, the crude guanidine hydrochloride product is added to the reaction kettle at a ratio of 1:1 with water, and the same amount of sodium hydroxide as the free ammonium in the crude product is added. The mixture is dissolved by stirring, filtered, and the mother liquor is depressurized to remove about 50% water. Crystallization, filtration of industrial grade products with a purity greater than 99%.
Refining again: The technical grade product:water is added into the reaction kettle at a ratio of 1:1, and then the same amount of sodium hydroxide as the product is added, stirred and dissolved, the membrane is filtered, and the mother liquor is depressurized to remove about 50% water. Crystallization, filtration, detection of free amines <1.2%, then drying to pharmaceutical grade products with a purity of >99.5%.
2 Comparison of new and old production processes
In this paper, the use of ammonium carbonate instead of ammonia in the existing process as an additive in the production process brings many advantages:
1) The process is simple and the process conditions are easily controlled. Due to the solid-state reaction, the temperature and reaction rate of the melt reaction in the production process can be easily controlled. At the same time, liquid ammonia storage tanks, transmission pipelines and other facilities are reduced, and the production cost is greatly reduced. The production cost is reduced by about 200 yuan per ton;
2) The crude product quality is greatly improved. The purity of the crude product obtained by adopting the prior process is 88~92%, and the purity of the product obtained by adopting this technology is above 95%, which is a qualitative improvement for large-scale production, and the refining cost is greatly reduced;
3) Increased safety during production. Because there is no need for hazardous links such as liquid ammonia storage and transportation in the current production process, the safety in the production process is greatly increased.
3 Process Improvement
The morpholinium hydrochloride was produced by the melt-reaction method, but the initial yield was only about 70%. Through various improvements in the production process and equipment of the molten reaction method, the yield was increased to 93%~96%. At the same time, it also improves the product quality.
3.1 Improved resistance to stirring
Since the material is in powder form and has high stirring resistance, we replaced the original small motor (4kW) with a large motor (715kW) and welded the agitator shaft to the reducer shaft to improve the resistance of the agitator.
3.2 Improvements in Methods for Controlling Reaction Temperature
(1) Use internal and external cooling method to control temperature. External cooling method: According to needs, cooling water can be circulated through the reaction vessel jacket. Internal cooling method: The original method is to put all the materials into the tank at one time, a large number of materials react at the same time, and the heat is severely exothermic. The temperature is difficult to control, and the viscous material with unclear structure is easy to generate, resulting in low product yield, poor quality, or even entire the batch is scrapped. The mixture is fed into the reaction vessel in batches, so that the materials are batched and reacted. The amount of heat released is relatively small, which makes the reaction temperature easier to control. On the other hand, the subsequently added mixture can be used as a cooling material, and the reaction can be input as needed. Inside the tank, a certain internal cooling effect is achieved, so that the severe exothermic reaction temperature is well controlled.
 (2) In the initial stage of the reaction, due to the rapid exotherm and rapid temperature rise, there is a hysteresis in the temperature displayed by the thermometer in the warm package. Now the thermometer is directly inserted into the material to measure the temperature, so as to truly reflect the temperature rise and fall in the tank. Take effective measures in time to control the reaction temperature.
(3) In the unlikely event that the temperature cannot be controlled, if the temperature exceeds 210°C, remedial measures may be taken. That is, pouring proper amount of tap water into the tank, the water will vaporize immediately, and take away a lot of heat, which can immediately cool down the temperature and close the product. The rate and quality have little effect. Through the above improvements, the reaction temperature is effectively controlled, laying the foundation for improving product yield and quality.
3.3 Improvements of Pressure Filter
After washing the pressure filter with H2O, a considerable part of H2O remains in the interior of several filter tubes and at the bottom of the filter press. Since the guanidine hydrochloride is easily soluble in H2O, these H2O can dissolve many guanidine hydrochlorides so that they cannot crystallize in the crystallization tank. The bottom of the filter press is now equipped with a drain valve to maximize the discharge of water inside the filter press, thereby increasing the product yield.
3.4 Distilled water recycling improvements
In the purification of guanidine hydrochloride with distilled water, the use of fresh distilled water in conjunction with the distilled water recovered when the concentrated mother liquor is used, thus solving the problem of the source of distilled water, not only can make the use of recycled distilled water well, but also greatly reduce the generation of refined wastewater.
4 Conclusion
The Guanidine hydrochloride produced by the molten reaction method uses ammonium carbonate instead of the ammonia in the existing process as an auxiliary agent in the production process. The process is simple, the reaction process is easy to control, and the product purity is high.
Edited by Suzhou Yacoo Science Co., Ltd.