A low-temperature reaction device for preparing entecavir

Abstract

The utility model discloses a preparation entecavir low temperature reaction device relates to low temperature reaction device field, including main reation kettle and vice reation kettle, the inside of main reation kettle is provided with spiral coil pipe, and the liquid nitrogen is passed in spiral coil pipe, and the inside of vice reation kettle is provided with ethanol, and the ethanol in vice reation kettle is heated to the ethanol in kettle through heat medium, and main reation kettle is connected with vice reation kettle through centrifugal pump. The utility model discloses heat exchange of liquid nitrogen and material through spiral coil pipe in main reation kettle, can avoid that material temperature is partial too low, can avoid that liquid nitrogen vaporization entrains material and discharges to reation kettle outside, and the ethanol in vice reation kettle is passed into the jacket of main reation kettle and is implemented heating through centrifugal pump, on one hand, utilizes the feature of ethanol freezing point for -114.1 DEG C, and low temperature material will not cause ethanol solidification after jacket passes in ethanol, avoids damaging reation kettle jacket, on the other hand, vice reation kettle has the heating function, and can quickly implement heating operation to the low temperature material of main reation kettle.

Description

Technical Field

[0001] This utility model relates to the field of low-temperature reaction apparatus, and in particular to a low-temperature reaction apparatus for preparing entecavir. Background Technology

[0002] Entecavir, a guanine nucleoside analog with selective activity against hepatitis B virus (HBV), inhibits HBV polymerase and is primarily used to treat chronic HBV infection. The chemical name of entecavir is 2-amino-1,9-dihydro-9-[(1s,3r,4s)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purine-6-one monohydrate. The synthesis of this substance involves two key reactions requiring low-temperature reactions between -100℃ and -80℃. The synthesis of the intermediate entecavir 7 utilizes specific methyleneizing reagents, Narstl reagent and titanium tetrachloride, to convert the ketone group on the cyclopentane fragment into a methylene functional group, requiring a relatively low reaction temperature. Additionally, a low reaction temperature is also used in the final step of entecavir synthesis when debenzylidene protecting with boron trichloride.

[0003] The two-step cryogenic reaction in the synthesis of entecavir requires the reactor to operate at -100℃ to -80℃. The existing method to achieve this cryogenic condition requires the use of liquid nitrogen for cooling, which is usually done by adding liquid nitrogen directly to the materials. This method can cause the materials to become locally too cold and clump together, affecting the normal reaction. At the same time, the cryogenic liquid nitrogen rapidly vaporizes into nitrogen gas upon contact with the reactants, expands in volume, and carries the materials out of the reactor, polluting the environment and affecting the health of the operators. Moreover, the material temperature needs to be raised to room temperature (20℃ to 30℃) in the later stages of the reaction, which is difficult to achieve in practice. Utility Model Content

[0004] In order to overcome the above-mentioned defects of the prior art, the present invention provides a low-temperature reaction apparatus for preparing entecavir, so as to solve the problems existing in the background art.

[0005] This utility model provides the following technical solution: a low-temperature reaction apparatus for preparing entecavir, comprising a main reaction vessel and a secondary reaction vessel. The main reaction vessel is equipped with a spiral coil, through which liquid nitrogen is introduced to exchange heat with the reactants inside the vessel, thus cooling the reactants to a low temperature of -100℃ to -80℃. The secondary reaction vessel contains ethanol, which is heated by a heat transfer medium. The main reaction vessel is connected to the secondary reaction vessel via a centrifugal pump, which transports the heated ethanol to the main jacket surrounding the main reaction vessel for heat exchange. This allows the heating function of the secondary reaction vessel to be used to heat the reactants inside the main reaction vessel.

[0006] Preferably, the auxiliary reactor is provided with a secondary jacket for loading a heat transfer medium to heat the ethanol, and the main reactor is provided with a main jacket for loading the heated ethanol. The lower outlet of the auxiliary reactor is connected to the input end of a centrifugal pump, and the lower inlet of the main jacket is connected to the output end of the centrifugal pump. This allows the heated ethanol in the auxiliary reactor to be pumped to the main jacket of the main reactor via the centrifugal pump, thereby achieving the heating operation of the low-temperature material in the main reactor by the heated ethanol in the auxiliary reactor.

[0007] Preferably, the upper outlet of the main jacket is connected to the secondary reactor, so that the ethanol after heat exchange can be transported back to the secondary reactor for recycling.

[0008] Preferably, the main reactor includes a main reactor body, an upper head, and a main stirring shaft. The upper head is used to seal the main reactor body, and the main stirring shaft is located at the center of the main reactor body and is vertically arranged. A double-layer stirring paddle is connected to the main stirring shaft of the main reactor.

[0009] Preferably, the spiral coil is made of Hastelloy alloy, and the spiral coil is disposed between the main stirring shaft and the inner body of the main vessel, and the spiral coil is connected to the upper end cap.

[0010] Preferably, the double-layer impeller includes a main anchor impeller located at the bottom of the main impeller shaft and an impeller impeller located in the middle of the main impeller shaft.

[0011] Preferably, the secondary reactor includes a secondary reactor body and a secondary stirring shaft. The secondary stirring shaft is located at the center of the secondary reactor body and is vertically arranged. A secondary anchor-type stirring paddle is provided at the bottom of the secondary stirring shaft of the secondary reactor.

[0012] Preferably, both the inner body of the main vessel and the upper end cap are made of stainless steel, and the surfaces of both the inner body of the main vessel and the upper end cap are coated with polytetrafluoroethylene anti-corrosion material.

[0013] Preferably, the inner body of the secondary reactor and the secondary jacket are both made of stainless steel.

[0014] Compared with the prior art, the beneficial effects of this utility model are as follows: 1. This utility model uses liquid nitrogen to exchange heat with the material through the spiral coil of the main reactor, which can avoid the material temperature from being too low in some areas and also prevent the liquid nitrogen from vaporizing and carrying the material out of the reactor.

[0015] 2. This utility model adopts the heating function of the auxiliary reactor. Ethanol in the auxiliary reactor is introduced into the jacket of the main reactor through a centrifugal pump to raise the temperature. On the one hand, taking advantage of the fact that the freezing point of ethanol is -114.1℃, the low-temperature material will not cause the ethanol to solidify after the ethanol is introduced into the jacket, thus avoiding damage to the reactor jacket; on the other hand, the auxiliary reactor has a heating function, which can quickly raise the temperature of the low-temperature material in the main reactor.

[0016] 3. This utility model utilizes a spiral coil and a jacket to load different heat exchange media, so that the heating and cooling heat exchange media do not come into direct contact, thus preventing freezing at low temperatures. At the same time, the spiral coil and jacket of the main reactor have a large heat exchange area, thereby improving the efficiency of heat exchange and shortening the cooling and heating time. It is not only easy to operate, but also has good industrial application value.

[0017] 4. The main reactor wall of this utility model is coated with polytetrafluoroethylene anti-corrosion material, which has good acid and alkali resistance. The spiral coil of the main reactor is made of Hastelloy alloy, which can withstand both low temperature liquid nitrogen and acidic corrosive materials. Attached Figure Description

[0018] Figure 1 This is a schematic diagram of the spiral coil structure of this utility model.

[0019] Figure 2 This is a schematic diagram of the connection structure between the main reactor and the auxiliary reactor of this utility model.

[0020] The attached diagram is labeled as follows: 1. Main reactor; 2. Auxiliary reactor; 3. Main reactor interior; 4. Upper head; 5. Main stirring shaft; 6. Main anchor-type agitator; 7. Impeller-type agitator; 8. Spiral coil; 9. Main jacket; 10. Auxiliary reactor interior; 11. Auxiliary stirring shaft; 12. Auxiliary anchor-type agitator; 13. Auxiliary jacket; 14. Centrifugal pump. Detailed Implementation

[0021] The preferred embodiments of the present invention will now be described in detail with reference to the accompanying drawings, so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby providing a clearer and more definite definition of the scope of protection of the present invention.

[0022] This invention provides a low-temperature reaction apparatus for preparing entecavir, such as... Figure 1-2 As shown, the reactor includes a main reactor 1 and a secondary reactor 2. The main reactor 1 is equipped with a spiral coil 8. Liquid nitrogen is introduced into the spiral coil 8 to exchange heat with the reactants inside the reactor and cool them down. This is used to perform a low-temperature reaction of the reactants at -100℃ to -80℃. The secondary reactor 2 is equipped with ethanol. The ethanol in the secondary reactor 2 is heated by a heat transfer medium. It should be noted that the heat transfer medium is a medium for transporting heat energy. In this embodiment, the heat transfer medium can be hot water or steam.

[0023] Furthermore, the main jacket of the main reactor 1 is connected to the auxiliary reactor 2 via a centrifugal pump 14, which delivers the heated ethanol to the main jacket of the main reactor 1 for heat exchange, so as to use the heating function of the auxiliary reactor 2 to heat the reaction materials inside the main reactor 1.

[0024] This application uses liquid nitrogen to exchange heat with the material through the spiral coil of the main reactor, which can avoid both localized low material temperature and prevent liquid nitrogen vaporization from carrying material out of the reactor.

[0025] The main reactor of this application is convenient for low-temperature operation through spiral coils, but it is very difficult to raise the material temperature to room temperature (20℃~30℃) in the later stage of the reaction. This application adopts a heating function of the auxiliary reactor. Ethanol in the auxiliary reactor is introduced into the jacket of the main reactor through a centrifugal pump to raise the temperature. On the one hand, taking advantage of the fact that the freezing point of ethanol is -114.1℃, the low-temperature material will not cause the ethanol to solidify after the ethanol is introduced into the jacket, thus avoiding damage to the reactor jacket; on the other hand, the auxiliary reactor has a heating function, which can quickly raise the temperature of the low-temperature material in the main reactor.

[0026] Furthermore, a secondary jacket 10 is provided around the auxiliary reactor 2 for loading hot water or steam to heat the ethanol, and a main jacket 9 is provided around the main reactor 1 for loading the heated ethanol. The lower outlet of the auxiliary reactor 2 is connected to the input end of the centrifugal pump 14, and the lower inlet of the main jacket 9 is connected to the output end of the centrifugal pump 14, so that the hot ethanol in the auxiliary reactor 2 is transported to the main jacket 9 of the main reactor 1 through the centrifugal pump 14, thereby realizing the heating operation of the low-temperature material in the main reactor 1 by the hot ethanol in the auxiliary reactor 2.

[0027] This application utilizes spiral coils and jackets to load different heat exchange media, preventing direct contact between the heating and cooling heat exchange media and thus preventing freezing at low temperatures. At the same time, the spiral coils and jackets of the main reactor have a large heat exchange area, thereby improving the efficiency of heat exchange and shortening the cooling and heating time. This not only makes the operation convenient but also has good industrial application value.

[0028] Furthermore, the upper outlet of the main jacket 9 is connected to the auxiliary reactor 2, so that the ethanol after heat exchange can be transported back to the auxiliary reactor 2 for recycling.

[0029] Furthermore, the main reactor 1 includes a main reactor body 3, an upper head 4, and a main stirring shaft 5. The upper head 4 is used to seal the main reactor body 3. The main stirring shaft 5 is located at the center of the main reactor body 3 and is vertically arranged. A double-layer stirring paddle is connected to the main stirring shaft 5 of the main reactor 1. The double-layer stirring paddle includes a main anchor-type stirring paddle 6 located at the bottom of the main stirring shaft 5 and an impeller-type stirring paddle 7 located in the middle of the main stirring shaft 5. The double-layer stirring paddle improves the stirring effect on low-temperature, high-viscosity materials.

[0030] Furthermore, the spiral coil 8 is made of Hastelloy alloy, which can withstand both low-temperature liquid nitrogen and acidic corrosive materials. The spiral coil 8 is located between the main stirring shaft 5 and the inner body 3 of the main vessel, and is connected to the upper end cap 4.

[0031] Furthermore, the secondary reactor 2 includes a secondary reactor body 10 and a secondary stirring shaft 11. The secondary stirring shaft 11 is located at the center of the secondary reactor body 10 and is vertically arranged. A secondary anchor-type stirring paddle 12 is provided at the bottom of the secondary stirring shaft 11 of the secondary reactor 2.

[0032] Furthermore, both the main reactor inner body 3 and the upper head 4 are made of stainless steel. The surfaces of both the main reactor inner body 3 and the upper head 4 are coated with polytetrafluoroethylene (PTFE) anti-corrosion material. The PTFE anti-corrosion material coating on the main reactor wall provides good acid and alkali resistance. Simultaneously, the temperature difference between the main reactor inner wall and the jacket is small, and the low-temperature liquid nitrogen does not directly contact the main reactor inner wall, avoiding unnecessary damage to the coated PTFE anti-corrosion material.

[0033] Furthermore, both the inner body 10 of the auxiliary vessel and the auxiliary jacket 13 are made of stainless steel.

[0034] Several points should be noted: First, in the description of this application, it should be noted that, unless otherwise specified and limited, the terms "installation", "connection" and "linkage" should be interpreted broadly, and can be mechanical or electrical connection, or internal connection between two components, or direct connection. "Up", "down", "left", "right", etc. are only used to indicate relative positional relationship. When the absolute position of the described object changes, the relative positional relationship may change. The above description is only a preferred embodiment of the present utility model. The protection scope of the present utility model is not limited to the above embodiments. Any equivalent modifications or changes made by those skilled in the art based on the content disclosed in the present utility model should be included in the protection scope recorded in the claims.

Claims

1. A low-temperature reaction apparatus for preparing entecavir, characterized in that, The reactor includes a main reactor (1) and a secondary reactor (2). The main reactor (1) is equipped with a spiral coil (8) inside. Liquid nitrogen is introduced into the spiral coil (8) to exchange heat with the reaction material inside the reactor and cool it down. This is used to carry out a low-temperature reaction of the reaction material from -100℃ to -80℃. The secondary reactor (2) is equipped with ethanol inside. The ethanol in the secondary reactor (2) is heated by a heat transfer medium. The main reactor (1) is connected to the secondary reactor (2) through a centrifugal pump (14) to transport the heated ethanol to the outer main jacket (9) of the main reactor (1) for heat exchange. The heating function of the secondary reactor (2) is used to heat the reaction material inside the main reactor (1).

2. The low-temperature reaction apparatus for preparing entecavir according to claim 1, characterized in that: The auxiliary reactor (2) is provided with an auxiliary jacket (13) for loading a heat medium to heat ethanol. The main reactor (1) is provided with a main jacket (9) for loading heated ethanol. The lower outlet of the auxiliary reactor (2) is connected to the input end of a centrifugal pump (14), and the lower inlet of the main jacket (9) is connected to the output end of the centrifugal pump (14). The hot ethanol in the auxiliary reactor (2) is transported to the main jacket (9) of the main reactor (1) by the centrifugal pump (14) so ​​as to realize the heating operation of the low temperature material in the main reactor (1) by the hot ethanol in the auxiliary reactor (2).

3. The low-temperature reaction apparatus for preparing entecavir according to claim 1, characterized in that: The upper outlet of the main jacket (9) is connected to the sub-reactor (2), and the ethanol after heat exchange is transported back to the sub-reactor (2) for recycling.

4. The low-temperature reaction apparatus for preparing entecavir according to claim 1, characterized in that: The main reactor (1) includes a main reactor body (3), an upper head (4), and a main stirring shaft (5). The upper head (4) is used to seal the main reactor body (3). The main stirring shaft (5) is located at the center of the main reactor body (3) and is vertically arranged. A double-layer stirring paddle is connected to the main stirring shaft (5) of the main reactor (1).

5. The low-temperature reaction apparatus for preparing entecavir according to claim 4, characterized in that: The spiral coil (8) is made of Hastelloy alloy. The spiral coil (8) is located between the main stirring shaft (5) and the inner body of the main vessel (3), and the spiral coil (8) is connected to the upper end cap (4).

6. The low-temperature reaction apparatus for preparing entecavir according to claim 4, characterized in that: The main reactor (1) has a double-layer agitator, including a main anchor agitator (6) located at the bottom of the main agitator shaft (5) and an impeller agitator (7) located in the middle of the main agitator shaft (5).

7. The low-temperature reaction apparatus for preparing entecavir according to claim 1, characterized in that: The secondary reactor (2) includes a secondary reactor body (10) and a secondary stirring shaft (11). The secondary stirring shaft (11) is located at the center of the secondary reactor body (10) and is vertically arranged. A secondary anchor-type stirring paddle (12) is provided at the bottom of the secondary stirring shaft (11) of the secondary reactor (2).

8. The low-temperature reaction apparatus for preparing entecavir according to claim 4, characterized in that: The main vessel inner body (3) and the upper end cap (4) are both made of stainless steel, and the surfaces of the main vessel inner body (3) and the upper end cap (4) are coated with polytetrafluoroethylene anti-corrosion material.

9. The low-temperature reaction apparatus for preparing entecavir according to claim 7, characterized in that: The inner body (10) and the jacket (13) of the auxiliary vessel are both made of stainless steel.

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