CN114195770A - Preparation method and device of posaconazole - Google Patents
Preparation method and device of posaconazole Download PDFInfo
- Publication number
- CN114195770A CN114195770A CN202111651018.4A CN202111651018A CN114195770A CN 114195770 A CN114195770 A CN 114195770A CN 202111651018 A CN202111651018 A CN 202111651018A CN 114195770 A CN114195770 A CN 114195770A
- Authority
- CN
- China
- Prior art keywords
- activated carbon
- cylinder
- posaconazole
- decoloring
- tank body
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Water Treatment By Sorption (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of posaconazole preparation, and particularly relates to a preparation method and a device of posaconazole; the device comprises a frame assembly, wherein a crude product dissolving device, a mixed liquid decoloring device and a solution crystallization device are arranged on the frame assembly, the mixed liquid decoloring device comprises an activated carbon decoloring cylinder, a hollow rotating rod is rotatably connected in the activated carbon decoloring cylinder, the lower end of the hollow rotating rod is connected with a connecting disc hollow rotating rod, the outer circular surface of the hollow rotating rod is provided with a helical blade, the lower end of the activated carbon decoloring cylinder is also provided with a waste material discharge pipe, and the upper end of the activated carbon decoloring cylinder is connected with an activated carbon feeding machine; according to the refining method of posaconazole, which is disclosed by the invention, the designed mixed liquid decoloring device can automatically discharge the invalid activated carbon after decoloring each pair of mixed liquid with the set volume, and then automatically perform adsorption decoloring under the action of new activated carbon particles, so that all the mixed liquid can be effectively ensured to be completely adsorbed and decolored, and the purity of the whole refined posaconazole is effectively ensured.
Description
Technical Field
The invention belongs to the technical field of posaconazole preparation, and particularly relates to a preparation method and a preparation device of posaconazole.
Background
Posaconazole is a second-generation triazole antifungal drug which is newly found at present, and is favored due to the characteristics of broad spectrum, high efficiency and low toxicity. The use of posaconazole organic compounds as a pharmaceutical in clinical settings requires very high purity, the control of various types of impurities in pharmaceutical compounds below pharmacopoeia standards, compliance with marketing standards is a complex and delicate process. The structure of posaconazole is complex, 4 chiral centers are involved in molecules, the compound can be obtained through multi-step chemical reactions, and a series of impurities are introduced in the synthetic process, wherein the impurities comprise: an unreacted intermediate; impurities introduced in the starting materials and intermediates; impurities generated by side reactions during the synthesis process; intermediates and degradation impurities of posaconazole. Therefore, the crude product of posaconazole needs to be refined and purified before being used as a medicine.
The invention patent with the application number of CN2019111374701 discloses a refining method of posaconazole, which comprises the following steps: dissolving the crude product of posaconazole in mixed solvents of ethyl acetate and acetone to completely dissolve the posaconazole; adding active carbon for decolorization, filtering, cooling the filtrate for crystallization, and growing crystal; filtering and washing the filtered solid with acetone, and vacuum drying to obtain the refined posaconazole. Although the refining method of posaconazole disclosed by the invention can realize the purification processing of the crude posaconazole product and can enable the purity of posaconazole to reach more than 99.9%, the active carbon decoloring process in the method is particularly important, the active carbon needs to be replaced in time after being used for a period of time, otherwise, the active carbon particles lose the adsorption decoloring effect, and due to the factors of equipment, the method needs to continuously interrupt the decoloring process to replace the active carbon in the industrial refining process of posaconazole, so that the refining efficiency of the whole posaconazole is greatly reduced. Therefore, aiming at the defects in the existing refining process of posaconazole, the application provides a preparation method and a device of posaconazole to solve the defects.
Disclosure of Invention
The invention aims to overcome the defect that the existing refining process of posaconazole is limited by equipment, the decoloring process needs to be interrupted continuously to replace active carbon, and the refining efficiency of the whole posaconazole is greatly reduced.
The invention is realized by the following technical scheme:
a preparation method of posaconazole comprises the following steps:
1) injecting a solvent into the dissolving tank, then quantitatively adding the crude posaconazole into the solvent through a crude product feeding machine, and quickly dissolving the crude posaconazole under the action of a stirring motor;
2) easily introducing the dissolved mixture into an activated carbon decolorizing cylinder, introducing the mixed solution into the lower end of the activated carbon decolorizing cylinder along a hollow rotating rod, then upwards flowing along a helical blade, repeatedly contacting with activated carbon particles in the flowing process, adsorbing and decolorizing, and replacing 0.6-1.4kg of activated carbon after decolorizing every 20-30L of the mixed solution;
3) introducing the filtrate subjected to adsorption and decoloration into a crystallization kettle for cooling, then crystallizing at the temperature of-2-4 ℃, and carrying out crystal liquid separation on the fully crystallized material;
4) and washing the separated crystal, and drying in vacuum after washing to obtain the refined posaconazole.
Preferably, the solvent is one or more of ethyl acetate and acetone.
Preferably, the temperature at which the crude posaconazole is dissolved is between 26 and 32 ℃.
A preparation device used in the posaconazole preparation method is the equipment in step 1-3, and comprises a rack assembly, and is characterized in that a crude product dissolving device, a mixed solution decoloring device and a solution crystallizing device are sequentially arranged at the upper end of the rack assembly, and a control box is further arranged at the front end of the rack assembly;
wherein, the crude product dissolving device comprises a dissolving tank body, the upper end opening of the dissolving tank body is connected with a tank body flange, the tank body flange is connected with a tank body cover through a fastening bolt, one end of the tank body cover is provided with a crude product feeding machine, the tank body cover positioned at the opposite side of the crude product feeding machine is provided with a solvent injection pipe, the circle center of the upper surface of the tank body cover is provided with a stirring motor, the output shaft of the stirring motor is connected with a stirring shaft extending into the dissolving tank body, the upper end of the stirring shaft is connected with a plurality of groups of stirring rods, the lower end of the stirring shaft is connected with a material turning blade, the left end and the right end of the inner wall of the dissolving tank body are both connected with vertical guide strips, the lower end of the dissolving tank body is provided with a filter screen frame, the upper surface of the filter screen frame is paved with a filter screen, and the two ends of the filter screen frame are provided with limit openings matched with the guide strips, a circular hole penetrating through the stirring shaft is formed in the circle center of the filter screen frame, a bearing disc is arranged on the stirring shaft below the filter screen frame, the lower end of the dissolving tank body is connected with a first liquid conveying pipe, a first liquid valve is arranged at the end part, close to the dissolving tank body, of the first liquid conveying pipe, and a first liquid conveying pump is arranged on the first liquid conveying pipe;
the mixed liquid decoloring device comprises an activated carbon decoloring cylinder, an upper end opening of the activated carbon decoloring cylinder is connected with a cylinder cover through a flange, the end part of a first liquid conveying pipe is connected with the circle center of the cylinder cover, the inner wall of the circle center of the cylinder cover is provided with a sealing bearing, a hollow rotating rod is rotatably connected in the sealing bearing, the circle center of a lower end opening of the hollow rotating rod is connected with a connecting disc through a plurality of connecting rods which are circumferentially arranged, the lower end of the activated carbon decoloring cylinder is provided with a rotating motor, an output shaft of the rotating motor extends into the bottom of an inner cavity of the activated carbon decoloring cylinder to be connected with the connecting disc, the outer circular surface of the hollow rotating rod is provided with a helical blade which is attached to the inner wall of the activated carbon decoloring cylinder, the lower end of the activated carbon decoloring cylinder is also provided with a waste material discharge pipe, a sealing valve is arranged on the waste material discharge pipe, and the upper end of the activated carbon decoloring cylinder is connected with an activated carbon feeding machine, the upper end of the activated carbon decoloring barrel is also connected with a second infusion tube, and a second infusion pump is arranged on the second infusion tube;
the solution crystallization device comprises a crystallization kettle, a cooling medium jacket is arranged on the outer surface of the crystallization kettle, an inlet pipe and a discharge pipe are respectively arranged at the upper end and the lower end of the cooling medium jacket, a driving motor is arranged at the top end of the crystallization kettle, the lower end of an output shaft of the driving motor extends into the crystallization kettle and is connected with a rotating shaft, the lower end of the rotating shaft is connected with a scraping plate which is attached to the inner wall of the crystallization kettle, the lower end of the crystallization kettle is connected with a discharge pipe, a material valve is arranged on the discharge pipe, and the lower end of the discharge pipe is connected with a crystal liquid separation device.
As the concrete setting of above-mentioned scheme, the liquid crystal separator is including the pay-off barrel that the slope set up, and the interlude of pay-off barrel is connected with the lower extreme of arranging the material pipe, the terminal surface of pay-off barrel is provided with the separation motor, the end connection that the output shaft of separation motor stretched into in the pay-off barrel has the separation spiral leaf, and the surface of separation spiral leaf has seted up a large amount of waterlogging caused by excessive rainfall holes, the end that inclines down of pay-off barrel is connected with the fluid-discharge tube, the last slope end of pay-off barrel is connected with row brilliant pipe.
In a further arrangement of the above scheme, a filter screen layer is further arranged at the upper end of the liquid discharge pipe.
According to the scheme, the outer side surface of the dissolving tank body is further provided with a heating and heat-preserving jacket, and the upper end and the lower end of the heating and heat-preserving jacket are respectively connected with a heat medium inlet pipe and a heat medium outlet pipe.
As a further arrangement of the above scheme, the upper end of the rotating shaft is also provided with a plurality of groups of stirring rods.
As the concrete setting of above-mentioned scheme, the frame assembly is including the last roof that is used for installing dissolving tank body, active carbon decoloration section of thick bamboo and crystallization kettle, four corners of the lower surface of going up the roof all are connected with the stabilizer blade, four lower extreme between the stabilizer blade still is provided with the bottom plate, first transfer pump and second transfer pump all set up on the bottom plate.
As the concrete setting of above-mentioned scheme, crude material loading machine and active carbon material loading machine all include a storage hopper, the lower extreme of storage hopper is connected with the auger feeder, the end connection of auger feeder has the unloading pipe.
Has the advantages that:
1) according to the refining method of posaconazole, the designed mixed liquid decoloring device can automatically discharge the invalid activated carbon after decoloring each pair of mixed liquid with the set volume, and then automatically perform adsorption decoloring under the action of new activated carbon particles, so that all the mixed liquid can be effectively and completely adsorbed and decolored, and the purity of posaconazole obtained by the whole refining process is effectively ensured.
2) The preparation device disclosed by the invention has a compact integral structure, realizes the processes of dissolving the crude posaconazole, adsorbing and decoloring by using the active carbon and cooling and crystallizing, and can be used for quickly and conveniently replacing the active carbon in the decoloring process without the operation of operators, so that the refining efficiency of posaconazole is greatly improved.
3) The crystal liquid separation device obliquely arranges the mixture in the feeding cylinder, when the crystal liquid mixture enters the feeding cylinder, the separation spiral blade has an obstruction effect on crystals so that the crystals cannot flow to the lower end of the feeding cylinder, the liquid can be discharged from the liquid discharge pipe through the draining holes on the spiral under the action of self gravity, after the liquid is discharged, the separation spiral blade is started to rotate the separation spiral blade and discharge the internal crystals from the crystal discharge pipe, so that the solid-liquid separation after crystallization is realized.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art that other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is a flow chart of the steps of the process for the preparation of posaconazole according to the invention;
FIG. 2 is a schematic view of a first-angle perspective structure of the manufacturing apparatus of the present invention;
FIG. 3 is a schematic view of a second angular perspective structure of the manufacturing apparatus of the present invention;
FIG. 4 is a schematic view showing the internal plan structure of a dissolving tank in a manufacturing apparatus according to the present invention;
FIG. 5 is a schematic view of the three-dimensional structure of a tank cover, a crude product feeder, a stirring shaft and the like in the preparation apparatus of the present invention;
FIG. 6 is a schematic perspective view of a filter frame, a filter screen, etc. in the manufacturing apparatus of the present invention;
FIG. 7 is a perspective semi-sectional view of a mixed liquid decoloring apparatus in the manufacturing apparatus of the present invention;
FIG. 8 is a schematic perspective view of a cartridge cover and a seal bearing in the manufacturing apparatus of the present invention;
FIG. 9 is a plan view of the inside of a mixed liquid decolorizer of the manufacturing apparatus of the present invention during the flow of the liquid;
FIG. 10 is a schematic perspective view of a hollow rotary rod, a connecting disk, a helical blade, etc. in a manufacturing apparatus according to the present invention;
FIG. 11 is a schematic view showing the internal plan structure of a solution crystallization apparatus in a manufacturing apparatus according to the present invention.
Wherein:
100-a crude product dissolving device, 101-a dissolving tank body, 102-a tank body flange, 103-a tank body cover, 104-a crude product feeding machine, 1041-a storage hopper, 1042-an auger feeding machine, 105-a solvent injection pipe, 106-a stirring motor, 107-a stirring shaft, 108-a stirring rod, 109-a stirring blade, 110-a guide strip, 111-a filter screen frame, 1111-a limiting port, 1112-a round hole, 112-a filter screen, 113-a receiving disc, 114-a first liquid conveying pipe, 115-a first liquid valve, 116-a first liquid conveying pump and 117-a heating and heat-preserving jacket;
200-mixed liquid decolorization device, 201-activated carbon decolorization cylinder, 202-cylinder cover, 203-sealing bearing, 204-hollow rotating rod, 205-connecting rod, 206-connecting disc, 207-rotating motor, 208-helical blade, 209-waste material discharge pipe, 210-sealing valve, 211-activated carbon feeder, 212-second liquid conveying pipe, 213-second liquid conveying pump;
300-a solution crystallization device, 301-a crystallization kettle, 302-a cooling medium jacket, 303-a driving motor, 304-a rotating shaft, 305-a scraping plate, 306-a crystal liquid separation device, 3061-a feeding cylinder, 3062-a separation motor, 3063-a separation spiral blade, 3064-a liquid discharge pipe, 3065-a crystallization discharge pipe, 3066-a filter screen layer and 307-a material valve;
400-frame assembly, 401-upper top plate, 402-support leg, 403-bottom plate and 500-control box.
Detailed Description
In order to make the technical solutions better understood by those skilled in the art, the technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application, and it is obvious that the described embodiments are only partial embodiments of the present application, but not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.
Moreover, the terms "mounted," "disposed," "provided," "connected," and "sleeved" are to be construed broadly. For example, it may be a fixed connection, a removable connection, or a unitary construction; can be a mechanical connection, or an electrical connection; may be directly connected, or indirectly connected through intervening media, or may be in internal communication between two devices, elements or components. The specific meanings of the above terms in the present invention can be understood by those of ordinary skill in the art according to specific situations.
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present application will be described in detail with reference to the accompanying drawings 1 to 11, in conjunction with the embodiments.
Example 1
Embodiment 1 discloses a preparation method of posaconazole, which comprises the following refining steps:
the method comprises the following steps: injecting a solvent into the dissolving tank, then quantitatively adding the crude posaconazole into the solvent through a crude product feeding machine, and rapidly dissolving the crude posaconazole under the action of a stirring motor, wherein the solvent is ethyl acetate, the mass ratio of the crude posaconazole to the crude posaconazole is 1: 8, and the temperature of the crude posaconazole during dissolving is controlled at 30 ℃.
Step two: and easily introducing the mixture obtained after dissolution into an activated carbon decoloring cylinder, enabling the mixed solution to enter the lower end of the activated carbon decoloring cylinder along a hollow rotating rod, then enabling the mixed solution to flow upwards along a helical blade, repeatedly contacting with activated carbon particles in the flowing process, adsorbing and decoloring, and replacing 0.8kg of activated carbon after decoloring every 26L of the mixed solution.
Step three: introducing the filtrate subjected to adsorption and decoloration into a crystallization kettle for cooling, then crystallizing at the temperature of-1 ℃, and carrying out crystal liquid separation on the fully crystallized material;
step four: and washing the separated crystal with acetone, and drying in vacuum after washing to obtain the refined posaconazole.
Example 2
Embodiment 1 discloses a preparation method of posaconazole, which comprises the following refining steps:
the method comprises the following steps: injecting a solvent into the dissolving tank, then quantitatively adding the crude posaconazole into the solvent through a crude product feeding machine, and rapidly dissolving the crude posaconazole under the action of a stirring motor, wherein the solvent is acetone, the mass ratio of the crude posaconazole to the crude posaconazole is 1: 6.8, and the temperature of the crude posaconazole during dissolving is controlled to be 32 ℃.
Step two: and the mixture obtained after dissolution is easily introduced into an activated carbon decoloring cylinder, the mixed solution enters the lower end of the activated carbon decoloring cylinder along a hollow rotating rod, then flows upwards along a helical blade, repeatedly contacts with activated carbon particles in the flowing process, adsorbs and decolors, and 1.1kg of activated carbon is replaced after every 22L of the mixed solution is decolored.
Step three: introducing the filtrate subjected to adsorption and decoloration into a crystallization kettle for cooling, then crystallizing at the temperature of 0 ℃, and carrying out crystal liquid separation on the fully crystallized material;
step four: and washing the separated crystal with acetone, and drying in vacuum after washing to obtain the refined posaconazole.
To sum up, in the refining methods of posaconazole disclosed in embodiments 1 and 2, the designed mixed liquid decolorization device can automatically discharge the failed activated carbon after decolorizing each pair of mixed liquid with a set volume, and then automatically perform adsorption decolorization under the action of new activated carbon particles, which can effectively ensure that all mixed liquid is completely adsorbed and decolorized, thereby effectively ensuring the purity of posaconazole obtained by the whole refining.
Example 3
Embodiment 3 discloses a manufacturing apparatus used in steps 1 to 3 of embodiment 1 or embodiment 2, referring to fig. 2 and fig. 3, comprising a frame assembly 400, wherein the frame assembly 400 comprises an upper top plate 401, supporting legs 402 are connected to four corners of the lower surface of the upper top plate 401, and a bottom plate 403 is further disposed at the lower end between the four supporting legs 402. A crude product dissolving device 100, a mixed liquid decoloring device 200 and a solution crystallization device 300 are sequentially arranged on an upper top plate 401 on the rack assembly 400, and a control box 500 is further arranged at the front end of the rack assembly 400.
Referring to fig. 4, fig. 5 and fig. 6, the crude product dissolving device 100 includes a dissolving tank 101, a tank flange 102 is connected to an upper end opening of the dissolving tank 101, the tank flange 102 is connected to a tank cover 103 through a fastening bolt, a crude product feeder 104 is disposed at one end of the tank cover 103, specifically, the crude product feeder 104 includes a storage hopper 1041, an auger feeder 1042 is connected to a lower end of the storage hopper 1041, a discharging pipe is connected to an end of the auger feeder 1042, the discharging pipe penetrates through the tank cover 103, and the crude posaconazole in the storage hopper 1041 can be quantitatively discharged into the dissolving tank 101 through the action of the auger feeder 1042. Meanwhile, a solvent injection pipe 105 is arranged on the tank cover 103 on the opposite side of the crude product feeding machine 104, and a solvent can be injected into the solvent injection pipe 105 to be mixed and dissolved with the crude posaconazole product.
In addition, in order to accelerate the dissolving speed of the crude posaconazole product, a stirring motor 106 is arranged at the center of the circle of the upper surface of the tank cover 103, an output shaft of the stirring motor 106 is connected with a stirring shaft 107 extending into the dissolving tank 101, the upper end of the stirring shaft 107 is connected with a plurality of groups of stirring rods 108, and the lower end of the stirring shaft 107 is connected with a stirring blade 109. Both ends all are connected with vertical gib block 110 about the inner wall of dissolving tank body 101, and the lower extreme of dissolving tank body 101 is provided with filter screen frame 111, and filter screen 112 has been laid to filter screen frame 111 upper surface, and filter screen frame 111's both ends are seted up with gib block 110 assorted spacing mouth 1111, and the round hole 1112 of passing the (mixing) shaft is seted up to the centre of a circle of filter screen frame 111, is provided with on the (mixing) shaft 107 that is located filter screen frame 111 below and accepts dish 113. The above-mentioned agitating unit through setting up can accelerate the dissolving rate of posaconazole crude in the solvent, and the filter screen 112 of laying on this filter screen frame 111 can connect undissolved impurity to carry out abundant filtration simultaneously, can take out the clearance together with jar body lid 103, rabbling mechanism and filter screen frame 111 from dissolving jar body 101 during clearance again. In order to ensure the solubility of the crude posaconazole product, a heating and heat-insulating jacket 117 is further arranged on the outer side surface of the dissolving tank body 101, the upper end and the lower end of the heating and heat-insulating jacket 117 are respectively connected with a heat medium inlet pipe and a heat medium outlet pipe, and the solvent can be heated by injecting heat-conducting oil with a certain temperature into the heating and heat-insulating jacket 117.
A first infusion tube 114 is connected to the lower end of the dissolution tank 101, a first liquid valve 115 is provided at the end of the first infusion tube 114 close to the dissolution tank 101, and a first infusion pump 116 is provided on the first infusion tube 114.
Referring to fig. 7, 8, 9 and 10, the mixed liquid decoloring apparatus 200 includes an activated carbon decoloring barrel 201, an upper end opening of the activated carbon decoloring barrel 201 is connected with a barrel cover 202 through a flange, and an end of the first infusion tube 114 is connected with a center of the barrel cover 202. A sealing bearing 203 is arranged on the inner wall of the center of the circle of the cylinder cover 202, a hollow rotating rod 204 is connected in the sealing bearing 203 in a rotating mode, and a connecting disc 206 is connected to the center of the circle of the lower end opening of the hollow rotating rod 204 through a plurality of connecting rods 205 arranged in the circumferential direction. The lower end of the activated carbon decoloring cylinder 201 is provided with a rotating motor 207, an output shaft of the rotating motor 207 extends into the bottom of an inner cavity of the activated carbon decoloring cylinder 201 and is connected with a connecting disc 206, the outer circular surface of the hollow rotating rod 204 is provided with a helical blade 208 which is attached to the inner wall of the activated carbon decoloring cylinder 201, the lower end of the activated carbon decoloring cylinder 201 is also provided with a waste material discharge pipe 209, the waste material discharge pipe 209 is provided with a sealing valve 210, the upper end of the activated carbon decoloring cylinder 201 is connected with an activated carbon feeding machine 211, specifically, the specific structure of the activated carbon feeding machine 211 is the same as that of the crude product feeding machine 104, the liquid comprises a storage hopper 1041 for storing activated carbon, the lower end of the storage hopper 1041 is connected with an auger feeding machine 1042, the end part of the auger feeding machine 1042 is connected with a discharge pipe, and the discharge pipe is communicated with the upper end of the activated carbon decoloring cylinder 201. In addition, a second liquid conveying pipe 212 is connected to the upper end of the activated carbon decoloring cylinder 201, and a second liquid conveying pump 213 is provided in the second liquid conveying pipe 212.
The mixed solution decoloring device 200 disclosed in this embodiment injects the mixed solution from the upper end of the hollow rotating rod 204, discharges the mixed solution from the lower end of the hollow rotating rod 204 to the periphery, flows to the upper end of the activated carbon decoloring barrel 201 along the direction of the helical blade 208 after discharging, and fully contacts with the activated carbon in the helical blade 208 during the flowing process. Meanwhile, after the activated carbon loses the adsorption decoloration effect for a period of time, the mixed liquid is stopped being injected into the activated carbon, then the sealing valve 210 on the waste material discharge pipe 209 is opened, the rotating motor 207 is started to enable the hollow rotating rod 204 to rotate, then the activated carbon in the activated carbon decoloration cylinder 201 is discharged along the opened waste material discharge pipe 209, and meanwhile, the activated carbon feeding machine 211 recharges new activated carbon.
Referring to fig. 11, the solution crystallization apparatus 300 includes a crystallization kettle 301, a cooling medium jacket 302 is disposed on an outer surface of the crystallization kettle 301, an inlet pipe and an outlet pipe are disposed at upper and lower ends of the cooling medium jacket 302, respectively, and a low-temperature cooling medium (such as ice water or a small amount of liquid nitrogen) can be injected into the cooling medium jacket 302 through the inlet pipe. A driving motor 303 is arranged at the top end of the crystallization kettle 301, the lower end of the output shaft of the driving motor 303 extending into the crystallization kettle 301 is connected with a rotating shaft 304, the lower end of the rotating shaft 304 is connected with a scraping plate 305 attached to the inner wall of the crystallization kettle 301, and meanwhile, in order to accelerate the uniform cooling of the filtrate during crystallization, a plurality of groups of stirring rods are also arranged at the upper end of the rotating shaft 304. The lower end of the crystallization kettle 301 is connected with a discharge pipe, the discharge pipe is provided with a material valve 307, and the lower end of the discharge pipe is connected with a crystal liquid separation device 306.
Specifically, the crystal liquid separation device 306 includes a feeding cylinder 3061 disposed in an inclined manner, a middle section of the feeding cylinder 3061 is connected to a lower end of the discharging pipe, a separation motor 3062 is disposed on an end surface of the feeding cylinder 3061, a separation spiral blade 3063 is connected to an end portion of the separation motor 3062 extending into the feeding cylinder 3061, a large number of draining holes are formed in the surface of the separation spiral blade 3063, a liquid discharge pipe 3064 is connected to a downward inclined end of the feeding cylinder 3061, and a crystal discharge pipe 3065 is connected to an upper inclined end of the feeding cylinder 3061. Further, a filter mesh layer 3066 is provided at the upper end of the drain pipe 3064. The above-mentioned crystal liquid separation device 306 sets the feeding cylinder 3061 obliquely, when the material valve 307 is opened, the crystal liquid mixture enters the feeding cylinder 3061, the separation spiral blade 3063 hinders the crystal and makes it unable to roll towards the lower end of the feeding cylinder 3061, and the liquid can be discharged from the liquid discharge pipe 3064 under the self gravity, after the liquid is discharged, the separation spiral blade 3063 is started again to make the separation spiral blade 3063 rotate, and the crystal inside is discharged from the crystal discharge pipe 3065, and then the product is obtained.
The present invention is not limited to the above preferred embodiments, and any modifications, equivalent substitutions and improvements made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A preparation method of posaconazole adopts a preparation device for preparation, and is characterized by comprising the following steps:
1) injecting a solvent into the dissolving tank, then quantitatively adding the crude posaconazole into the solvent through a crude product feeding machine, and quickly dissolving the crude posaconazole under the action of a stirring motor;
2) easily introducing the dissolved mixture into an activated carbon decolorizing cylinder, introducing the mixed solution into the lower end of the activated carbon decolorizing cylinder along a hollow rotating rod, then upwards flowing along a helical blade, repeatedly contacting with activated carbon particles in the flowing process, adsorbing and decolorizing, and replacing 0.6-1.4kg of activated carbon after decolorizing every 20-30L of the mixed solution;
3) introducing the filtrate subjected to adsorption and decoloration into a crystallization kettle for cooling, then crystallizing at the temperature of-2-4 ℃, and carrying out crystal liquid separation on the fully crystallized material;
4) and washing the separated crystal, and drying in vacuum after washing to obtain the refined posaconazole.
2. The method for preparing posaconazole according to claim 1, wherein the solvent is one or more of ethyl acetate and acetone.
3. The method for preparing posaconazole as claimed in claim 1, wherein the crude posaconazole is dissolved at a temperature of 26-32 ℃.
4. A preparation device used in the posaconazole preparation method of any one of claims 1 to 3, wherein the preparation device is the equipment in step 1 to 3 and comprises a rack assembly (400), and is characterized in that a crude product dissolving device (100), a mixed solution decoloring device (200) and a solution crystallizing device (300) are sequentially arranged at the upper end of the rack assembly (400), and a control box (500) is further arranged at the front end of the rack assembly (400);
wherein, the crude product dissolving device (100) comprises a dissolving tank body (101), the upper end opening of the dissolving tank body (101) is connected with a tank body flange (102), the tank body flange (102) is connected with a tank body cover (103) through a fastening bolt, one end of the tank body cover (103) is provided with a crude product feeding machine (104), the tank body cover (103) positioned at the opposite side of the crude product feeding machine (104) is provided with a solvent injection pipe (105), the circle center of the upper surface of the tank body cover (103) is provided with a stirring motor (106), the output shaft of the stirring motor (106) is connected with a stirring shaft (107) extending into the dissolving tank body (101), the upper end of the stirring shaft (107) is connected with a plurality of groups of stirring rods (108), the lower end of the stirring shaft (107) is connected with a material turning blade (109), the left end and the right end of the inner wall of the dissolving tank body (101) are both connected with vertical guide strips (110), a filter screen frame (111) is arranged at the lower end of the dissolving tank body (101), a filter screen (112) is laid on the upper surface of the filter screen frame (111), limiting ports (1111) matched with the guide strips (110) are formed in two ends of the filter screen frame (111), a round hole (1112) penetrating through a stirring shaft is formed in the circle center of the filter screen frame (111), a bearing disc (113) is arranged on the stirring shaft (107) located below the filter screen frame (111), a first infusion tube (114) is connected to the lower end of the dissolving tank body (101), a first liquid valve (115) is arranged at the end part, close to the dissolving tank body (101), of the first infusion tube (114), and a first infusion pump (116) is arranged on the first infusion tube (114);
the mixed liquid decoloring device (200) comprises an activated carbon decoloring cylinder (201), an upper end opening of the activated carbon decoloring cylinder (201) is connected with a cylinder cover (202) through a flange, the end part of a first infusion tube (114) is connected with the circle center of the cylinder cover (202), the inner wall of the circle center of the cylinder cover (202) is provided with a sealing bearing (203), a hollow rotating rod (204) is rotatably connected in the sealing bearing (203), the circle center of a lower end opening of the hollow rotating rod (204) is connected with a connecting disc (206) through a plurality of connecting rods (205) which are circumferentially arranged, the lower end of the activated carbon decoloring cylinder (201) is provided with a rotating motor (207), an output shaft of the rotating motor (207) extends into the bottom of an inner cavity of the activated carbon decoloring cylinder (201) to be connected with the connecting disc (206), the outer circular surface of the hollow rotating rod (204) is provided with spiral blades (208) which are attached to the inner wall of the activated carbon decoloring cylinder (201), the lower end of the activated carbon decolorizing cylinder (201) is also provided with a waste discharging pipe (209), a sealing valve (210) is arranged on the waste discharging pipe (209), the upper end of the activated carbon decolorizing cylinder (201) is connected with an activated carbon feeding machine (211), the upper end of the activated carbon decolorizing cylinder (201) is also connected with a second liquid conveying pipe (212), and a second liquid conveying pump (213) is arranged on the second liquid conveying pipe (212);
solution crystallization device (300) is including crystallization kettle (301), the surface of crystallization kettle (301) is provided with cooling medium jacket (302), the upper and lower end of cooling medium jacket (302) is provided with admission pipe and discharge pipe respectively, the top of crystallization kettle (301) is provided with driving motor (303), the output shaft of driving motor (303) stretches into in crystallization kettle (301) lower extreme and is connected with rotation axis (304), the lower extreme of rotation axis (304) is connected with scrapes board (305) with crystallization kettle (301) inner wall looks laminating, the lower extreme of crystallization kettle (301) is connected with row material pipe, be provided with material valve (307) on the row material pipe, the lower extreme of row material pipe is connected with crystallization liquid separator (306).
5. The apparatus for preparing posaconazole according to claim 4, wherein the crystal liquid separating device (306) comprises a feeding cylinder (3061) which is arranged in an inclined manner, the middle section of the feeding cylinder (3061) is connected with the lower end of the discharging pipe, a separating motor (3062) is arranged on the end surface of the feeding cylinder (3061), the end part of the output shaft of the separating motor (3062) extending into the feeding cylinder (3061) is connected with a separating spiral blade (3063), the surface of the separating spiral blade (3063) is provided with a large number of draining holes, the lower inclined end of the feeding cylinder (3061) is connected with a liquid discharging pipe (3064), and the upper inclined end of the feeding cylinder (3061) is connected with a discharging pipe (3065).
6. The apparatus for preparing posaconazole according to claim 5, wherein the upper end of the liquid discharge pipe (3064) is further provided with a filtering net layer (3066).
7. The apparatus for preparing posaconazole according to claim 4, wherein a heating and heat-preserving jacket (117) is further disposed on an outer side of the dissolving tank (101), and a heat medium inlet pipe and a heat medium outlet pipe are respectively connected to an upper end and a lower end of the heating and heat-preserving jacket (117).
8. The apparatus for use in the process of preparing posaconazole according to claim 4, wherein the upper end of the rotating shaft (304) is also provided with a plurality of sets of stirring rods.
9. The apparatus for preparing posaconazole according to claim 4, wherein the rack assembly (400) comprises an upper top plate (401) for mounting the dissolving tank (101), the activated carbon decolorizing cylinder (201) and the crystallization kettle (301), wherein four corners of the lower surface of the upper top plate (401) are connected with supporting legs (402), a bottom plate (403) is further arranged at the lower end between the four supporting legs (402), and the first infusion pump (116) and the second infusion pump (213) are arranged on the bottom plate (403).
10. The apparatus for preparing posaconazole according to claim 4, wherein the crude product feeder (104) and the activated carbon feeder (211) each comprise a storage hopper (1041), the lower end of the storage hopper (1041) is connected with an auger feeder (1042), and the end of the auger feeder (1042) is connected with a discharge pipe.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111651018.4A CN114195770B (en) | 2021-12-30 | 2021-12-30 | Preparation method and device of posaconazole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111651018.4A CN114195770B (en) | 2021-12-30 | 2021-12-30 | Preparation method and device of posaconazole |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114195770A true CN114195770A (en) | 2022-03-18 |
| CN114195770B CN114195770B (en) | 2023-08-08 |
Family
ID=80657399
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111651018.4A Active CN114195770B (en) | 2021-12-30 | 2021-12-30 | Preparation method and device of posaconazole |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114195770B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115554731A (en) * | 2022-10-24 | 2023-01-03 | 连云港贵科药业有限公司 | Preparation method of gemcitabine |
| CN117959963A (en) * | 2024-03-28 | 2024-05-03 | 世联生物工程无锡有限公司 | Active calcium powder dissolving device |
| CN117959963B (en) * | 2024-03-28 | 2024-05-28 | 世联生物工程无锡有限公司 | Active calcium powder dissolving device |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106147831A (en) * | 2016-09-21 | 2016-11-23 | 重庆方盛净化设备有限公司 | Waste oil fast purification decolouring integrated device |
| CN107019953A (en) * | 2017-05-27 | 2017-08-08 | 湖北华丹医药科技股份有限公司 | A kind of positive pressure-off charcoal conveying device of bulk drug crystallizing tank liquid material |
| CN110204626A (en) * | 2019-06-17 | 2019-09-06 | 日照职业技术学院 | A kind of device and method sea cucumber polysaccharide separation and refined |
| CN211284202U (en) * | 2019-11-28 | 2020-08-18 | 威海厚普生物科技有限公司 | New salt forming system for high-purity loxoprofen sodium |
| CN112824400A (en) * | 2019-11-20 | 2021-05-21 | 华创合成制药股份有限公司 | Preparation method of posaconazole |
| CN112898279A (en) * | 2019-11-19 | 2021-06-04 | 爱之源生物科技有限公司 | Refining method of high-purity posaconazole |
-
2021
- 2021-12-30 CN CN202111651018.4A patent/CN114195770B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106147831A (en) * | 2016-09-21 | 2016-11-23 | 重庆方盛净化设备有限公司 | Waste oil fast purification decolouring integrated device |
| CN107019953A (en) * | 2017-05-27 | 2017-08-08 | 湖北华丹医药科技股份有限公司 | A kind of positive pressure-off charcoal conveying device of bulk drug crystallizing tank liquid material |
| CN110204626A (en) * | 2019-06-17 | 2019-09-06 | 日照职业技术学院 | A kind of device and method sea cucumber polysaccharide separation and refined |
| CN112898279A (en) * | 2019-11-19 | 2021-06-04 | 爱之源生物科技有限公司 | Refining method of high-purity posaconazole |
| CN112824400A (en) * | 2019-11-20 | 2021-05-21 | 华创合成制药股份有限公司 | Preparation method of posaconazole |
| CN211284202U (en) * | 2019-11-28 | 2020-08-18 | 威海厚普生物科技有限公司 | New salt forming system for high-purity loxoprofen sodium |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115554731A (en) * | 2022-10-24 | 2023-01-03 | 连云港贵科药业有限公司 | Preparation method of gemcitabine |
| CN117959963A (en) * | 2024-03-28 | 2024-05-03 | 世联生物工程无锡有限公司 | Active calcium powder dissolving device |
| CN117959963B (en) * | 2024-03-28 | 2024-05-28 | 世联生物工程无锡有限公司 | Active calcium powder dissolving device |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114195770B (en) | 2023-08-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114195770B (en) | Preparation method and device of posaconazole | |
| CN211069102U (en) | Cooling crystallizer convenient to handle that industrial production used | |
| CN215353293U (en) | Efficient compound fertilizer granulation mixing arrangement | |
| CN211536626U (en) | Active carbon adsorption device for product decoloration | |
| CN206227610U (en) | A kind of stirred filter tank of honey | |
| CN113717114B (en) | 2-acetylpyrazine continuous recrystallization device, method and application thereof | |
| CN110559681A (en) | Device and method for preparing high-purity p-cresol | |
| CN114130348A (en) | Continuous synthesis system and continuous synthesis method for metformin hydrochloride | |
| CN215841710U (en) | Benzoic acid purification crystallization device | |
| CN212632398U (en) | High-purity filtering type medical batching tank | |
| CN115554731A (en) | Preparation method of gemcitabine | |
| CN217312330U (en) | 3-aminoisoxazole active carbon decoloration heat filter equipment | |
| CN111729341A (en) | Freezing crystallizer mechanism | |
| CN220075194U (en) | Crude resin refining device for chemical resin production | |
| CN112924215B (en) | Plant root system soil sampling equipment | |
| CN216473249U (en) | Equipment for extracting gypenosides by enzyme treatment | |
| CN219297446U (en) | Horse oil extraction jar with rabbling mechanism | |
| CN220860699U (en) | N-acetylneuraminic acid crystallization tank | |
| CN104262418A (en) | Production method of crystallized water threose | |
| CN219272204U (en) | Purification device is used in heparin sodium production | |
| CN219072138U (en) | Automatic carbon fiber decoloration device of sodium azide | |
| CN216755469U (en) | Liquid medicine decoloration device | |
| CN218961812U (en) | Forced internal circulation crystallization tank flow guiding device | |
| CN214286768U (en) | Crystallization device of medical intermediate sartanbiphenyl | |
| CN220860702U (en) | Device for preparing cooling crystallization of phloroglucinol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |