CN113248412A - Preparation method of florfenicol - Google Patents

Abstract

A preparation method of florfenicol comprises the steps of reacting D-ethyl ester with methanol and potassium borohydride to obtain a product in the first step; the product obtained in the first step is used for obtaining a product obtained in the second step, namely an intermediate cyclic compound under the action of dichloroacetonitrile and glacial acetic acid, dichloromethane, diethylamine and hexafluoropropylene are used for preparing a product obtained in the third step, namely an Ishikawa fluorination reagent, dichloromethane is used as a solvent, the product obtained in the second step and the product obtained in the third step react to obtain a product obtained in the fourth step, namely a fluorination reaction liquid, and the product obtained in the fourth step is transferred to a hydrolysis kettle; and (3) adding water and sodium acetate into the product obtained in the step four and placing the product into a hydrolysis kettle, heating and distilling the product, distilling the dichloromethane, adding the last batch of final crystallization mother liquor after the dichloromethane is distilled, heating and reacting to obtain most of isopropanol and water, and cooling and centrifugally separating to obtain a florfenicol crude product. Refining to obtain pure product, and using crystallization mother liquor. And a set of auxiliary feeding device is also arranged and is used for effectively adding the potassium borohydride in the step one and treating the hydrogen in the dissolving process.

Description

Preparation method of florfenicol

Technical Field

The invention relates to the technical field of pharmaceutical chemicals, in particular to a preparation method of florfenicol.

Background

Florfenicol is also called florfenicol, is a special broad-spectrum antibiotic for animals, and is mainly used for bacterial diseases of animals such as cattle, pigs, chickens, ducks, fishes and the like. The florfenicol has a structure similar to thiamphenicol, but the antibacterial activity is 10 times higher than that of thiamphenicol; and the antibacterial broad spectrum and adverse reaction are obviously better than thiamphenicol. Florfenicol has now become the primary antimicrobial drug for animal species. Due to the excellent drug effect, the application prospect is very wide. The synthesis of florfenicol has therefore been receiving great attention.

The florfenicol structural formula is shown below:

currently, in the industrial preparation of florfenicol, p-methylsulfonylbenzaldehyde, glycine and the like are mainly used as starting raw materials, and the (2S,3R) -p-methylsulfonylphenylserine ethyl ester (D-ethyl ester) is prepared through steps of condensation, esterification, resolution and the like. And then preparing oxazoline by reduction and reaction with benzonitrile on the basis of taking the D-ethyl ester as a raw material, and carrying out fluorination, hydrolysis, dichloroacetylation and other steps under the action of an Ishikawa reagent.

The current florfenicol industrial production route must use a key intermediate D-ethyl ester, the steps of copper sulfate complexation preparation of amino acid copper salt, chiral resolution and the like are needed for producing the D-ethyl ester, a large amount of copper sulfate wastewater is generated in the production process, 50% of raw materials are wasted in the chiral resolution process, and the use cost of the D-ethyl ester is high. Equivalent Ishikawa reagent is required in the fluorination reaction step, and the utilization rate of fluorine atoms in the reagent is low, and the cost is high. In conclusion, the existing florfenicol production line has high production cost and generates a large amount of wastewater which is difficult to treat, so that the industrial production line with high yield and less other wastes is valuable to find. In the prior art, the method for preparing florfenicol is often insufficient in overall yield, or the operation process is too complicated although the yield is high, and the method cannot be used for large-scale production.

Due to the nature of the molecule, this method cannot be generalized to the synthesis of other similar structures. This is determined by the originality of the preparation, the higher yields and the irreproducibility of the shorter reaction times obtained in numerous trials, other routes having substantially no higher yields or acceptable reaction times.

In addition, the prior art has the problem that the prior preparation technology basically needs to add a large amount of KBH4 or NaBH4 into D-ethyl ester or a derivative thereof, but the process generates an ignorable amount of hydrogen, and the problem also exists in design reaction.

Disclosure of Invention

The invention aims to solve the problems that the florfenicol preparation in the prior art lacks a preparation route with high yield, convenient operation and less other wastes, and secondly, the problem that no targeted discharge means of hydrogen is caused by using KBH4 is solved.

The invention claims a charging auxiliary device for preparing florfenicol, which is characterized in that: comprises a reduction reaction kettle, an air inlet part, an air outlet part, a funnel part, a cross rod part, an ultrasonic device, a left supporting part and a right supporting part.

The reduction reaction kettle is provided with an upper opening, an air inlet, an air outlet, a feed inlet and a stirrer, wherein the upper opening, the air inlet, the air outlet and the feed inlet are respectively suitable for an upper opening cover, an air inlet cover, an air outlet cover and a feed inlet cover; the upper port is positioned right above the reduction reaction kettle, the air inlet and the feed inlet are positioned on the inclined plane on the right side of the upper port, the air outlet is positioned on the inclined plane on the left side of the upper port, and the axis of the feed inlet is parallel to the axis of the reduction reaction kettle.

The air inlet part is provided with an air inlet pipe, an air inlet pump, an air inlet glass pipe, an air inlet plug and a first fixing part; the air inlet pipe is made of polyester materials, the tail end of the air inlet pipe is tightly sleeved at the outer end of the air inlet glass pipe, the air inlet glass pipe is inserted into the through hole in the center of the air inlet plug and is clamped by the first fixing part tightly attached to the inner side of the through hole, and the inner end of the air inlet glass pipe is provided with a bent hook part.

The air outlet part is provided with an air outlet pipe, an air outlet pump, an air outlet glass pipe, an air outlet plug and a second fixing part; the air outlet pipe is made of polyester materials, the tail end of the air outlet pipe is tightly sleeved at the outer end of the air outlet glass pipe, the air outlet glass pipe is divided into a thin part, a large-diameter part and a horn part from outside to inside, the thin part is inserted into a through hole in the center of the air outlet plug, and the thin part is clamped by a second fixing part tightly attached to the inner side of the through hole.

The funnel part is provided with a sealing ring, a body part, a lower leakage part, a wide mouth, a convex rod, a support edge and a leakage net; the sealing washer is that silicon rubber makes, it possesses horizontally ring portion and interior cylindrical layer, outer cylindrical layer, interior cylindrical layer, the top edge of outer cylindrical layer all is connected with ring portion, the part thickening that has a through-hole and meet with the through-hole in the middle of the ring portion, the through-hole adaptation in the middle of somatic part external diameter and the ring portion, lower hourglass portion has the internal diameter of being no less than 1cm, the wide-mouth is connected in somatic part top, the somatic part right side of wide-mouth below has a welded connection's horizontally protruding pole, the somatic part outside of protruding pole below has outside outstanding round support reason, somatic part inside has one and weaves the hourglass net that the steel wire made.

The cross bar part is provided with a circular ring part, a left cross bar, a right cross bar and a lining; the middle of the transverse rod part is provided with a circular ring part, the inner side of the circular ring part is pasted with a lining, the inner diameter of the circular ring part is matched with the outer diameter of the body part, the supporting edge is supported by the upper edge of the circular ring part, and the left side and the right side of the circular ring part are respectively connected with the left transverse rod and the right transverse rod in a welded mode.

The ultrasonic device is provided with a vibration head, an energy converter, a generator, a power supply and a cable, wherein the vibration head is connected with the energy converter through the cable, a connecting wire of the vibration head and the energy converter is wrapped in the reinforced cable, the energy converter is connected with the generator, and the generator is powered by the power supply; the convex rod is inserted into the groove in the vibration head and is fixed by a plurality of groove screws.

The left supporting part is provided with a left rod, a left base, a left cylinder, a left shock absorber and a left central hole; the left supporting part is located on the left side of the funnel part, the left base is a cylindrical base with a screw hole in the middle, the lower end of the left rod is screwed into the screw hole and fixed, the upper end of the left rod is connected with a left cylinder in a welding mode, the left cylinder is a hollow cylinder with a horizontal axis, the left shock absorber is a polyurethane elastomer bonded in the left cylinder, and a left central hole which is horizontally suitable for the left cross rod to be inserted and fixed is formed in the center of the left shock absorber.

The right supporting part is provided with a right rod, a right base, a right cylinder, a right shock absorber and a right central hole; the right supporting part is positioned at the right side of the funnel part, the right base is a cylindrical base with a screw hole in the middle, the lower end of a right rod is screwed into the screw hole to be fixed, the upper end of the right rod is connected with a right cylinder in a welding mode, the right cylinder is a hollow cylinder with a horizontal axis, the right shock absorber is a polyurethane elastomer bonded in the right cylinder, and the center of the right shock absorber is provided with a right center hole with a horizontal plane suitable for the right cross rod to be inserted into and fixed.

The lower center of the reduction reaction kettle is provided with a stirrer which extends inwards.

Preferably, the upper opening, the air inlet, the air outlet, the feed inlet and the corresponding upper opening cover, the air inlet cover, the air outlet cover and the feed inlet cover are fastened or screwed. The flow rates of the air inlet pump and the air outlet pump are controlled to be 1-2L/min; the first fixing part and the second fixing part are made of polyurethane material gaskets; the average pore diameter of the screen is slightly larger than that of a 20-mesh screen; the air inlet glass tube and the air outlet glass tube are made of transparent and corrosion-resistant glass; the upper cover, the air inlet cover, the air outlet cover, the material inlet cover, the air inlet plug and the air outlet plug are made of any one of nylon PA, polytetrafluoroethylene or engineering plastic materials; the working frequency of the vibrating head is between 15KHZ and 100 KHZ; the cross rod part, the left supporting part and the right supporting part are made of stainless steel; the polyurethane elastomer has a Shore D hardness of 50 or more.

The preparation method of florfenicol is characterized by being carried out by utilizing the device and comprising the following steps of:

(1) installing and trial run: taking down an upper opening cover, an air inlet cover and an air outlet cover of the reduction reaction kettle, respectively installing an air inlet plug and an air outlet plug, installing an air inlet glass tube and an air outlet glass tube from the opened upper opening, respectively connecting the air inlet tube, an air inlet pump, an air outlet tube and an air outlet pump, covering the upper opening cover, introducing nitrogen at the speed of 1-2L/min by using an air inlet part, leading out gas at the same speed by using an air outlet part, and repeatedly opening and closing the upper opening until the opening and closing can not cause obvious change of air pressure; (2) a funnel part mounting step: the left supporting part and the right supporting part are arranged in front of and behind the funnel part, the charging port cover is removed and replaced by a sealing ring, the sealing ring is tightly sleeved on the charging port, the circular ring part is positioned right above the axis of the sealing ring, the funnel is inserted into the circular ring part, so that the supporting edge is attached to the circular ring part, the convex rod is inserted into a groove in the vibrating head and is fixed by a plurality of groove screws; the lower part of the body part adjacent to the circular part is wound and fixed by a plurality of circles of electrical tapes; (3) a reduction reaction step: putting D-p-methylsulfonylphenylserine ethyl ester and methanol into a reduction reaction kettle, stirring to dissolve the D-p-methylsulfonylphenylserine ethyl ester and the methanol, grinding potassium borocyanide to an average particle size of about 40 meshes, putting the ground potassium borocyanide into a funnel in batches, introducing nitrogen into an air inlet part at a speed of 1-2L/min, introducing gas out of an air outlet part at the same speed, controlling the reaction temperature to be not more than 30 ℃ by using jacket brine ice, continuing the process until the potassium borocyanide is added completely, removing the jacket brine ice after the potassium borohydride is completely added, naturally heating the system, introducing a little steam, continuously introducing nitrogen, controlling the temperature in the reaction kettle to be 60 ℃, and keeping the temperature for 5-7 hours; then evaporating most of methanol by decompression to obtain a reaction mixture in the third step; (4) a cyclization reaction step: transferring the reaction mixture obtained in the third step to a cyclization reaction kettle, cooling, adding glycerol into the reaction kettle, continuously distilling out most of the residual methanol under normal pressure, cooling the reaction mixture to about 40 ℃, dropwise adding glacial acetic acid, stirring for one hour after dropwise adding, continuously dropwise adding dichloroacetonitrile, heating to 55 ℃ after the dropwise adding is finished, keeping the temperature until solids are separated out, continuously preserving the temperature for 16-20 hours, adding water into the reaction mixture to separate out a large amount of solids, cooling to 15-25 ℃, performing centrifugal separation, and drying to obtain a cyclic compound intermediate; (5) a fluorinating agent preparation step: setting a fluorinating agent preparation kettle, adding dichloromethane and diethylamine into the kettle, introducing liquid nitrogen, cooling to below-30 ℃, starting introducing hexafluoropropylene, and stirring and keeping the current temperature for 1-2 hours after a preset amount of hexafluoropropylene is introduced to obtain an Ishikawa fluorinating agent; (6) a fluorination reaction step: setting a fluorination reaction kettle, weighing a dry cyclic compound intermediate, adding the dry cyclic compound intermediate into the fluorination reaction kettle, adding dichloromethane, stirring for dissolving, pumping an Ishikawa fluorination reagent into the fluorination reaction kettle, opening a jacket of the fluorination reaction kettle, heating by steam, controlling the reaction temperature to be 85-95 ℃, pressurizing to 4-5 atmospheric pressures in the kettle, carrying out heat preservation and pressure maintaining reaction for 2 hours, cooling to 25-35 ℃, and transferring all reaction mixtures into a hydrolysis kettle; (7) a hydrolysis reaction step: adding water and sodium acetate into a reaction mixture in a hydrolysis kettle, heating and distilling to evaporate dichloromethane, adding the previous batch of crystallization mother liquor obtained in the step (8) after the dichloromethane is evaporated, continuously heating to 75-85 ℃, reacting for 4 hours, continuously evaporating isopropanol and water after the reaction is finished until most of the isopropanol is evaporated to obtain a viscous mixture, cooling, and performing centrifugal separation to obtain a crude florfenicol product; (8) refining: taking a refining kettle for standby, adding a florfenicol crude product into a mixed solution of isopropanol and water in the refining kettle, heating until the crude product starts to be dissolved, keeping the current temperature for 30-60min, adding activated carbon for decolorization, filtering out waste activated carbon, cooling and crystallizing all filtrate, performing centrifugal separation, washing with water and drying to obtain a pure florfenicol product, and mechanically hydrolyzing a crystallization mother liquor in the next batch.

Preferably: in the step (1), nitrogen is introduced at a speed of 1.4-1.6L/min by using an air inlet part, and gas is led out at the same speed by using an air outlet part. In the step (3), nitrogen is introduced into the gas inlet part at the speed of 1.4-1.6L/min, gas is led out at the same speed by the gas outlet part, the reaction temperature is controlled not to exceed 30 ℃ by using jacket brine ice, the temperature in the reaction kettle is controlled to be 60 ℃, and the temperature is kept for 6 hours. In the step (4), the temperature of the reaction mixture is reduced to about 40 ℃, the temperature is raised to 55 ℃ after the addition, the heat preservation is continued for 18 hours, and the temperature is reduced to 20 ℃ for centrifugal separation. And (5) introducing liquid nitrogen, cooling to below-30 ℃, after introducing a preset amount of hexafluoropropylene, stirring and keeping the current temperature for 1.5 h. In the step (6), the reaction temperature is controlled at 90 ℃, the pressure in the kettle is increased to 4.5 atmospheric pressures, the temperature and pressure are kept for 2 hours for reaction, and the temperature is reduced to 30 ℃. In the step (7), the temperature is continuously heated to 80 ℃ and the reaction lasts for 4 hours. In step (8), the current temperature is maintained for 50 min.

Preferably, all of the foregoing reagents are chemically pure or purer. The water is deionized water, preferably double distilled water.

Compared with the prior art, the invention has the advantages that: the florfenicol preparation lacks a preparation route with high yield, convenient operation and less other wastes, and secondly solves the problem that hydrogen is not discharged in a targeted way due to the necessity of KBH 4.

First, in the prior art, the method for preparing florfenicol is often insufficient in the overall yield of less than 50%, which is a serious waste of the bitter D-ethyl ester and Ishikawa reagents, or the operation process is excessively complicated although the yield is high, which is not supposed to be applicable to large-scale production. The method solves the problem well, not only has high yield and can stably exceed 65%, but also basically does not generate the situation of low yield. And secondly, other wastes are generated less, mother liquor can be reused, the utilization rate is further improved, wastes which are difficult to treat are not generated basically in the method, the Ishikawa reagent is used basically and completely, D-ethyl ester is also used mostly, a large amount of waste gas and toxic substances are not generated, and the actual yield is further improved and promoted by reusing the mother liquor in the steps 7-8. And thirdly, no operation steps which are time-consuming and labor-consuming are needed, the operation is simple and extensive, the mass processing is convenient, diatomite is often needed for filtration assistance in other reactions, the pH value is adjusted, the HPLC detection reaction is complete, the time and the labor are consumed, the mass production is difficult to realize, the method does not need the steps, the operation is basically simple and intuitive, and common workers can also perform skillful operation. Fourthly, the problem of producing hydrogen has been properly solved, must use KBH4 to lead to necessarily producing a certain amount of hydrogen, and this hydrogen does not have targeted discharge means, but is not little hidden danger to industrial production, after all hydrogen concentration reaches certain degree and probably initiates the explosion, this application is taken out the hydrogen that produces with the mode of letting in inert gas and flowing ingeniously, the bell mouth of the glass pipe of giving vent to anger is close to the upper surface, be convenient for take out light hydrogen, inert gas this application can also play certain stable reaction and control temperature and avoid too high effect.

At present, no report of preparation of the product exists in the prior art, compared with a preparation method of similar substances, the method disclosed by the invention has the advantages that the steps are delicate, the utilization rate of raw materials in each step is very high, the method has great value to realize industrial production, the method disclosed by the invention is finely designed, the synthesis is effectively realized, the yield is high, 1220 kgD-p-methylsulfonylphenylserine ethyl ester can obtain 1000kg of 3-florfenicol, the yield is up to 65.75%, the steps are generally and conveniently operated, the industrial production is facilitated, the method has certain industrial production value and great economic value, the method disclosed by the invention embodies extremely strong invention conception and creativity through meticulously designing reaction steps and auxiliary devices, good preparation effect is obtained, no similar public information can be used for reference in the prior art, and the scheme disclosed by the invention has originality. In contrast, the applicant has tried most of the preparation methods in the prior art and found that basically the yield and the ease of operation are not compatible, and many methods with high nominal yield cannot be produced in large scale due to complicated steps, thereby seriously affecting the yield. The applicant tried a method in which no hydrogen is taken out from the unvented gas in step 3, and found that the hydrogen concentration is already over 1% after the reaction is completed, which is quite dangerous.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.

Figure 1 is a schematic of the overall scheme for the preparation of florfenicol.

Figure 2 is a schematic diagram of the synthetic variation of the main component for preparing florfenicol.

FIG. 3 is a schematic diagram of the Ishikawa reagent preparation.

FIG. 4 is a schematic view of the loading aid of the present invention.

Fig. 5 is a schematic sectional view of the intake portion composition.

Fig. 6 is a schematic sectional view of the gas outlet portion.

Figure 7 is a schematic cross-sectional view of the funnel.

Fig. 8 is a top view of the cross bar portion.

Fig. 9 is a schematic view of an ultrasound device.

Fig. 10 is a schematic view of the left and right support portions.

Reference numerals: the reduction reactor 1, the upper port 11, the air inlet 12, the air outlet 13, the charging port 14, the stirrer 15, the upper port cover 111, the air inlet cover 121, the air outlet cover 131, the charging port cover 141, the air inlet 2, the air inlet pipe 21, the air inlet pump 22, the air inlet glass pipe 23, the hook 231, the air inlet plug 24, the first fixing part 241, the air outlet part 3, the air outlet pipe 31, the air outlet pump 32, the air outlet glass pipe 33, the thin part 333, the large diameter part 331, the horn 332, the air outlet plug 34, the second fixing part 341, the funnel part 4, the sealing ring 41, the body part 42, the lower leakage part 43, the wide port 44, the convex rod 45, the support edge 46, the leakage net 47, the cross rod part 5, the circular ring part 51, the left cross rod 52, the right cross rod 53, the lining 54, the ultrasonic device 6, the vibration head 61, the transducer 62, the generator 63, the power supply 64, the cable 65, the left support part 7, the left rod 71, the left base 72, the left cylinder 73, the left damper 74, the left center hole 741, Right support 8, right rod 81, right base 82, right cylinder 83, right damper 84, right center hole 841.

Detailed Description

The preferred embodiments of the present invention will be described in detail below 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, and the scope of the present invention will be more clearly and clearly defined.

Example 1

The invention claims a charging auxiliary device for preparing florfenicol, which is characterized in that: comprises a reduction reaction kettle 1, an air inlet part 2, an air outlet part 3, a funnel part 4, a cross rod part 5, an ultrasonic device 6, a left support part 7 and a right support part 8.

The reduction reaction kettle 1 is provided with an upper opening 11, an air inlet 12, an air outlet 13, a feed inlet 14 and a stirrer 15, wherein the upper opening 11, the air inlet 12, the air outlet 13 and the feed inlet 14 are respectively matched with an upper opening cover 111, an air inlet cover 121, an air outlet cover 131 and a feed inlet cover 141; the upper opening 11 is positioned right above the reduction reaction kettle, the air inlet 12 and the feed inlet 14 are positioned on the inclined plane on the right side of the upper opening 11, the air outlet 13 is positioned on the inclined plane on the left side of the upper opening 11, and the axis of the feed inlet 14 is parallel to the axis of the reduction reaction kettle. The other settings of the reaction kettle adopt the general settings in the field, the vertical charging hole is used for the unhindered charging, and the charging hole vertical to the inclined plane is not easy to operate.

The air inlet part 2 is provided with an air inlet pipe 21, an air inlet pump 22, an air inlet glass pipe 23, an air inlet plug 24 and a first fixing part 241; the air inlet pipe is made of polyester materials, the tail end of the air inlet pipe 21 is tightly sleeved at the outer end of the air inlet glass pipe 23, the air inlet glass pipe 23 is inserted into a through hole in the center of the air inlet plug 24 and is clamped by a first fixing part 241 tightly attached to the inner side of the through hole, and the inner end of the air inlet glass pipe 23 is provided with a bent hook part 231. The air inlet pipe can be sleeved with a glass pipe by adopting some lubricating means and also plays a certain role in air tightness. The air inlet pipe is divided into two sections, namely a section from an air source to the pump and a section from the pump to the air inlet glass pipe, and the pump is provided with a flow meter to facilitate adjustment and observation.

The gas outlet part 3 is provided with a gas outlet pipe 31, a gas outlet pump 32, a gas outlet glass pipe 33, a gas outlet plug 34 and a second fixing part 341; the air outlet pipe 31 is made of polyester material, the tail end of the air outlet pipe 31 is tightly sleeved at the outer end of the air outlet glass pipe 33, the air outlet glass pipe 33 is divided into a thin part 333, a large-diameter part 331 and a horn part 332 from outside to inside, the thin part 333 is inserted into a through hole in the center of the air outlet plug 34, and the through hole is clamped by a second fixing part 341 tightly attached to the inner side of the through hole. The air outlet pipe can be sleeved with a glass pipe by adopting some lubricating means and also plays a certain role in air tightness. The pump is provided with a flow meter to facilitate adjustment and observation.

The funnel part 4 is provided with a sealing ring 41, a body part 42, a lower leakage part 43, a wide opening 44, a convex rod 45, a support edge 46 and a leakage net 47; sealing washer 41 is that silicon rubber makes, it possesses horizontally ring portion and interior cylindrical layer, outer cylindrical layer, interior cylindrical layer, the top edge of outer cylindrical layer all is connected with ring portion, the part thickening that has a through-hole and meet with the through-hole in the middle of the ring portion, the through-hole adaptation in the middle of somatic part external diameter and the ring portion, lower hourglass portion 43 has the internal diameter of being no less than 1cm, wide-mouth 44 connects in somatic part 42 top, somatic part 42 right side below wide-mouth 44 has a welded connection's horizontally protruding pole 45, the somatic part outside of protruding pole 45 below has outside outstanding round support edge 46, somatic part 42 inside has one and weaves the hourglass net 47 that the steel wire made. Except the sealing ring, the sealing ring is made of stainless steel or other alloy with similar properties.

The crossbar 5 comprises a circular ring part 51, a left crossbar 52, a right crossbar 53 and a lining 54; the middle of the transverse rod part 5 is provided with a circular ring part 51, a lining 54 is pasted on the inner side of the circular ring part 51, the inner diameter of the circular ring part 51 is matched with the outer diameter of the body part 42, the supporting edge 46 is supported by the upper edge of the circular ring part 42, and the left side and the right side of the circular ring part 51 are respectively connected with a cylindrical left transverse rod 52 and a cylindrical right transverse rod 53 in a welding mode. The left cross bar 52 and the right cross bar 53 can be pre-arranged through holes or blind holes inserted into the circular ring part 51, and then welded, so that the effect is stronger.

The ultrasonic device 6 is provided with a vibration head 61, a transducer 62, a generator 63, a power supply 64 and a cable 65, wherein the vibration head 61 is connected with the transducer 62 through the cable 65, a connecting line of the vibration head 61 and the transducer 62 is wrapped in the reinforcing cable 65, the transducer 62 is connected with the generator 63, and the generator 63 is powered by the power supply 64; the male rod 45 is inserted into a groove in the vibrating head 61 and is fixed by a plurality of groove screws 36. The power of the vibration head is between 20 and 100W, the frequency is an integer between 15KHZ and 100KHZ, the groove is matched with the vibration head, the vibration head is a cylinder, and the groove is also provided with at least two symmetrical through holes for the penetration of a groove screw and the penetration of a screw hole on the vibration head for fixation.

The left support portion 7 includes a left rod 71, a left base 72, a left tube 73, a left damper 74, and a left center hole 741; the left support part 7 is located at the left of the funnel part 4, the left base 72 is a cylindrical base with a screw hole in the middle, the lower end of the left rod 71 is screwed into the screw hole and fixed, the upper end of the left rod 71 is connected with the left cylinder 73 in a welding mode, the left cylinder is a hollow cylinder with a horizontal axis, the left shock absorber 74 is a polyurethane elastomer bonded in the left cylinder 73, and a left central hole 741 which is horizontal and suitable for the left cross rod 52 to be inserted and fixed is arranged at the center of the left shock absorber 74. The parts except the shock absorber are all made of stainless steel.

The right support part 8 is provided with a right rod 81, a right base 82, a right cylinder 83, a right damper 84 and a right center hole 841; the right supporting part 8 is positioned at the right side of the funnel part 4, the right base 82 is a cylindrical base with a screw hole in the middle, the lower end of a right rod 81 is screwed into the screw hole and fixed, the upper end of the right rod 81 is connected with a right cylinder 83 in a welding mode, the right cylinder is a hollow cylinder with a horizontal axis, a right shock absorber 84 is a polyurethane elastomer bonded in the right cylinder 83, and a right center hole 841 is formed in the center of the right shock absorber 84 and is horizontally suitable for the right cross rod 53 to be inserted and fixed. The parts except the shock absorber are all made of stainless steel.

The lower center of the reduction reaction kettle 1 is provided with a stirrer extending inwards.

Preferably, the upper opening 11, the air inlet 12, the air outlet 13, the filling opening 14 and the corresponding upper opening cover 111, the air inlet cover 121, the air outlet cover 131 and the filling opening cover 141 are fastened or screwed. The flow rates of the air inlet pump 22 and the air outlet pump 32 are controlled to be 1-2L/min, specifically 1.2, 1.4, 1.6 and 1.8; the first fixing portion 241 and the second fixing portion 341 are urethane material washers; the average pore diameter of the screen 47 is slightly larger than that of a 20-mesh sieve, so that when the particles are 40-mesh sieve in diameter, the particles are not easy to fall uniformly without vibration, and can fall at a certain speed regularly with vibration; the gas inlet glass tube 23 and the gas outlet glass tube 33 are made of transparent and corrosion-resistant glass; the upper cover 111, the air inlet cover 121, the air outlet cover 131, the material inlet cover 141, the air inlet plug 24 and the air outlet plug 34 are made of any one of nylon PA66, polytetrafluoroethylene or engineering plastic materials; the working frequency of the vibrating head is between 15KHZ and 100 KHZ; the cross rod part 5, the left support part 7 and the right support part 8 are made of stainless steel; the polyurethane elastomers have a shore D hardness of 50 or more, for example 55, 60, 65, 70.

Example 2

(1) Installing and trial run: taking down an upper opening cover, an air inlet cover and an air outlet cover of a reduction reaction kettle, respectively installing an air inlet plug and an air outlet plug, installing an air inlet glass tube (23) and an air outlet glass tube (33) from the opened upper opening, respectively connecting an air inlet tube (21), an air inlet pump (22), an air outlet tube (31) and an air outlet pump (32), covering the upper opening cover (111), introducing nitrogen at the speed of 1.4-1.6L/min by using an air inlet part, leading out gas at the same speed by using the air outlet part, repeatedly opening and closing the upper opening and monitoring until the air pressure is not obviously changed due to opening and closing; this step ensures the installation and the smooth flow of air.

(2) A funnel part mounting step: the left supporting part and the right supporting part are arranged in front of and behind the funnel part, the charging port cover is removed and replaced by a sealing ring, the sealing ring is tightly sleeved on the charging port, the circular ring part (51) is positioned right above the axis of the sealing ring, the funnel is inserted into the circular ring part, so that the supporting edge (46) is attached to the circular ring part (51), the convex rod (45) is inserted into a groove in the vibrating head (61), and the convex rod is fixed by a plurality of groove screws (36); the lower part of the body part adjacent to the circular part (51) is wound and fixed by electrical tape for a plurality of circles; the fixation is to make the funnel tightly attached to the supporting edge and not to shake.

(3) A reduction reaction step: putting D-p-methylsulfonylphenylserine ethyl ester and methanol into a reduction reaction kettle, stirring to dissolve the D-p-methylsulfonylphenylserine ethyl ester and the methanol, grinding potassium borocyanide to an average particle size of about 40 meshes, putting the ground potassium borocyanide into a funnel in batches, introducing nitrogen at the speed of 1.4-1.6L/min of an air inlet part, introducing gas at the same speed of an air outlet part, controlling the reaction temperature to be not more than 30 ℃ by using jacket ice salt water, continuing the process until the potassium borocyanide is added completely, removing the jacket ice salt water after the potassium borohydride is completely added, naturally heating the system, introducing a little steam, continuously introducing nitrogen, controlling the temperature in the reaction kettle to be 60 ℃, and keeping the temperature for 6 hours; then evaporating most of methanol by decompression to obtain a reaction mixture in the third step; batch here means to ensure that there is always material in the hopper to be fed in. After the charging, the charging port cover 141 is replaced to close the charging port. The little steam can be operated from the charging opening, and can also be added from a normally closed adding opening arranged after the pump on the air inlet pipe. The time for adding steam is, for example, several minutes.

(4) A cyclization reaction step: transferring the reaction mixture obtained in the third step to a cyclization reaction kettle, cooling, adding glycerol into the reaction kettle, continuously distilling out most of the residual methanol under normal pressure, cooling the reaction mixture to about 40 ℃, dropwise adding glacial acetic acid, stirring for one hour after dropwise adding, continuously dropwise adding dichloroacetonitrile, heating to 55 ℃ after completing addition, keeping the temperature until solids are separated out, continuously preserving heat for 18 hours, adding water into the reaction mixture to separate out a large amount of solids, cooling to 20 ℃, performing centrifugal separation, and drying to obtain a cyclic compound intermediate;

(5) a fluorinating agent preparation step: setting a fluorinating agent preparation kettle, adding dichloromethane and diethylamine into the kettle, introducing liquid nitrogen, cooling to below-30 ℃, starting introducing hexafluoropropylene, and stirring and keeping the current temperature for 1.5 hours after a preset amount of hexafluoropropylene is introduced to obtain an Ishikawa fluorinating agent;

(6) a fluorination reaction step: setting a fluorination reaction kettle, weighing a dry cyclic compound intermediate, adding the cyclic compound intermediate into the fluorination reaction kettle, adding dichloromethane, stirring for dissolving, pumping an Ishikawa fluorination reagent into the fluorination reaction kettle, opening a jacket of the fluorination reaction kettle, heating by steam, controlling the reaction temperature to be 90 ℃, pressurizing to 4.5 atmospheric pressure in the kettle, carrying out heat preservation and pressure maintaining reaction for 2 hours, cooling to 30 ℃, and transferring all reaction mixtures into a hydrolysis kettle;

(7) a hydrolysis reaction step: adding water and sodium acetate into a reaction mixture in a hydrolysis kettle, heating and distilling to evaporate dichloromethane, adding the last batch of crystallization mother liquor obtained in the step (8) after the dichloromethane is evaporated, continuously heating to 80 ℃, reacting for 4 hours, continuously evaporating isopropanol and water after the reaction is finished until most of the isopropanol is evaporated to obtain a viscous mixture, cooling, and performing centrifugal separation to obtain a crude florfenicol product;

(8) refining: taking a refining kettle for standby, adding a florfenicol crude product into a mixed solution of isopropanol and water in the refining kettle, heating until the crude product starts to be dissolved, keeping the current temperature for 50min, adding activated carbon for decolorization, filtering out waste activated carbon, cooling and crystallizing all filtrate, carrying out centrifugal separation, washing with water and drying to obtain a pure florfenicol product, and mechanically hydrolyzing a crystallization mother liquor in the next batch. The final yield of this example was about 65.74969% as D ethyl ester.

Example 3

(1) Installing and trial run: taking down an upper opening cover, an air inlet cover and an air outlet cover of a reduction reaction kettle, respectively installing an air inlet plug and an air outlet plug, installing an air inlet glass tube (23) and an air outlet glass tube (33) from the opened upper opening, respectively connecting an air inlet tube (21), an air inlet pump (22), an air outlet tube (31) and an air outlet pump (32), covering the upper opening cover (111), introducing nitrogen at the speed of 1.4-1.6L/min by using an air inlet part, leading out gas at the same speed by using the air outlet part, repeatedly opening and closing the upper opening and monitoring until the air pressure is not obviously changed due to opening and closing;

(2) a funnel part mounting step: the left supporting part and the right supporting part are arranged in front of and behind the funnel part, the charging port cover is removed and replaced by a sealing ring, the sealing ring is tightly sleeved on the charging port, the circular ring part (51) is positioned right above the axis of the sealing ring, the funnel is inserted into the circular ring part, so that the supporting edge (46) is attached to the circular ring part (51), the convex rod (45) is inserted into a groove in the vibrating head (61), and the convex rod is fixed by a plurality of groove screws (36); the lower part of the body part adjacent to the circular part (51) is wound and fixed by electrical tape for a plurality of circles;

(3) a reduction reaction step: putting 1220kg of D-p-methylsulfonylphenylserine ethyl ester and 5693kg of methanol into a reduction reaction kettle, stirring to dissolve the D-p-methylsulfonylphenylserine ethyl ester, grinding 260kg of potassium borocyanide to about 40 meshes of average particle size, putting the ground potassium borocyanide into a funnel in batches, introducing nitrogen into a gas inlet part at the speed of 1.6-1.8L/min, introducing gas out of a gas outlet part at the same speed, controlling the reaction temperature to be not more than 30 ℃ by using jacket ice salt water, continuing the process until the potassium borocyanide is completely added, removing the jacket ice salt water after adding the potassium boronate completely, naturally heating the system, introducing a little steam, continuously introducing the nitrogen, controlling the temperature in the reaction kettle to be 60 ℃, and preserving the temperature for 6 hours; then evaporating most of methanol by decompression to obtain a reaction mixture in the third step; batch here means to ensure that there is always material in the hopper to be fed in. After the charging, the charging port cover 141 is replaced to close the charging port.

(4) A cyclization reaction step: transferring the reaction mixture obtained in the third step to a cyclization reaction kettle, cooling, adding 3252kg of glycerol into the reaction kettle, continuously distilling out most of the residual methanol under normal pressure, cooling the reaction mixture to about 40 ℃, dropwise adding 122kg of glacial acetic acid, stirring for one hour after the dropwise addition is finished, continuously dropwise adding 545kg of dichloroacetonitrile, heating to 55 ℃ after the addition is finished, keeping the temperature until solids are separated out, continuously preserving the temperature for 18 hours, adding water into the reaction mixture to separate out a large amount of solids, cooling to 20 ℃, performing centrifugal separation, and drying to obtain a cyclic intermediate;

(5) a fluorinating agent preparation step: setting a fluorinating agent preparation kettle, adding 4065kg of dichloromethane and 350kg of diethylamine, introducing liquid nitrogen, cooling to below-30 ℃, starting to introduce 764kg of hexafluoropropylene, after introducing a predetermined amount of hexafluoropropylene, stirring and keeping the current temperature for 1.5h to obtain an Ishikawa fluorinating agent;

(6) a fluorination reaction step: setting a fluorination reaction kettle, weighing a dry cyclic compound intermediate, adding the dry cyclic compound intermediate into the fluorination reaction kettle, adding sufficient dichloromethane, stirring for dissolving, pumping all Ishikawa fluorination reagents into the fluorination reaction kettle, opening a jacket of the fluorination reaction kettle, heating by steam, controlling the reaction temperature at 90 ℃, pressurizing to 4.5 atmospheric pressure in the kettle, carrying out heat preservation and pressure maintaining reaction for 2 hours, cooling to 30 ℃, and transferring all reaction mixtures into a hydrolysis kettle;

(7) a hydrolysis reaction step: adding 4366kg of water and 488kg of sodium acetate into a reaction mixture in a hydrolysis kettle, heating and distilling, distilling to recover dichloromethane for the next batch, adding 3634kg of the previous batch of crystallization mother liquor obtained in the step (8) after distillation, continuously heating to 80 ℃, reacting for 4h, continuously distilling isopropanol and water after reaction, recovering at least 2195kg of isopropanol until most of the isopropanol is distilled to obtain a viscous mixture, cooling, and performing centrifugal separation to obtain a crude florfenicol product;

(8) refining: taking a refining kettle for standby, adding a florfenicol crude product into a mixed solution of 2496kg of isopropanol and 6894kg of water in the refining kettle, heating until the crude product is dissolved, keeping the current temperature for 50min, adding 44.7kg of activated carbon for decolorization, filtering waste activated carbon, recovering isopropanol not less than 1504kg, cooling and crystallizing all filtrate, carrying out centrifugal separation, washing with water and drying to obtain a pure product florfenicol, and mechanically hydrolyzing a crystallization mother liquor in the next batch. The final yield of this example was about 66.3177% as D ethyl ester.

Example 4

(1) Installing and trial run: taking down an upper opening cover, an air inlet cover and an air outlet cover of a reduction reaction kettle, respectively installing an air inlet plug and an air outlet plug, installing an air inlet glass tube (23) and an air outlet glass tube (33) from the opened upper opening, respectively connecting an air inlet tube (21), an air inlet pump (22), an air outlet tube (31) and an air outlet pump (32), covering the upper opening cover (111), introducing nitrogen at the speed of 1.4-1.6L/min by using an air inlet part, leading out gas at the same speed by using the air outlet part, repeatedly opening and closing the upper opening and monitoring until the air pressure is not obviously changed due to opening and closing;

(2) a funnel part mounting step: the left supporting part and the right supporting part are arranged in front of and behind the funnel part, the charging port cover is removed and replaced by a sealing ring, the sealing ring is tightly sleeved on the charging port, the circular ring part (51) is positioned right above the axis of the sealing ring, the funnel is inserted into the circular ring part, so that the supporting edge (46) is attached to the circular ring part (51), the convex rod (45) is inserted into a groove in the vibrating head (61), and the convex rod is fixed by a plurality of groove screws (36); the lower part of the body part adjacent to the circular part (51) is wound and fixed by electrical tape for a plurality of circles;

(3) a reduction reaction step: putting 1220kg of D-p-methylsulfonylphenylserine ethyl ester and 5693kg of methanol into a reduction reaction kettle, stirring to dissolve the D-p-methylsulfonylphenylserine ethyl ester, grinding 260kg of potassium borocyanide to an average particle size of about 40 meshes, putting the ground potassium borocyanide into a funnel in batches, introducing nitrogen at the speed of 1.6L/min of an air inlet part, introducing gas at the same speed of an air outlet part, controlling the reaction temperature to be not more than 30 ℃ by using jacket ice salt water, continuing the process until the potassium borocyanide is completely added, removing the jacket ice salt water after the potassium borohydride is completely added, naturally heating the system, slightly introducing steam, continuously introducing nitrogen, controlling the temperature in the reaction kettle to be 61 ℃, and preserving the temperature for 7 hours; then evaporating most of methanol by decompression to obtain a reaction mixture in the third step; batch here means to ensure that there is always material in the hopper to be fed in. After the charging, the charging port cover 141 is replaced to close the charging port.

(4) A cyclization reaction step: transferring the reaction mixture obtained in the third step to a cyclization reaction kettle, cooling, adding 3252kg of glycerol into the reaction kettle, continuously distilling out most of the residual methanol under normal pressure, cooling the reaction mixture to about 41 ℃, dropwise adding 122kg of glacial acetic acid, stirring for one hour after the dropwise addition is finished, continuously dropwise adding 545kg of dichloroacetonitrile, heating to 56 ℃ after the addition is finished, keeping the temperature until solids are separated out, continuously preserving the temperature for 20 hours, adding water into the reaction mixture to separate out a large amount of solids, cooling to 21 ℃, performing centrifugal separation, and drying to obtain a cyclic intermediate;

(5) a fluorinating agent preparation step: setting a fluorinating agent preparation kettle, adding 4065kg of dichloromethane and 350kg of diethylamine, introducing liquid nitrogen, cooling to below-31 ℃, starting to introduce 764kg of hexafluoropropylene, after introducing a predetermined amount of hexafluoropropylene, stirring and keeping the current temperature for 2h to obtain the Ishikawa fluorinating agent;

(6) a fluorination reaction step: setting a fluorination reaction kettle, weighing a dry cyclic compound intermediate, adding the dry cyclic compound intermediate into the fluorination reaction kettle, adding sufficient dichloromethane, stirring for dissolving, pumping all Ishikawa fluorination reagents into the fluorination reaction kettle, opening a jacket of the fluorination reaction kettle, heating by steam, controlling the reaction temperature to 88 ℃, pressurizing to 4.4 atmospheric pressures in the kettle, carrying out heat preservation and pressure maintaining reaction for 3 hours, cooling to 31 ℃, and transferring all reaction mixtures into a hydrolysis kettle;

(7) a hydrolysis reaction step: adding 4366kg of water and 488kg of sodium acetate into a reaction mixture in a hydrolysis kettle, heating and distilling, distilling to recover dichloromethane for the next batch, adding 3634kg of the previous batch of crystallization mother liquor obtained in the step (8) after distillation, continuously heating to 82 ℃, reacting for 5 hours, continuously distilling isopropanol and water after reaction, recovering at least 2195kg of isopropanol until most of the isopropanol is distilled to obtain a viscous mixture, cooling, and performing centrifugal separation to obtain a crude florfenicol product;

(8) refining: taking a refining kettle for standby, adding a florfenicol crude product into a mixed solution of 2496kg of isopropanol and 6894kg of water in the refining kettle, heating until the crude product is dissolved, keeping the current temperature for 50min, adding 44.7kg of activated carbon for decolorization, filtering waste activated carbon, recovering isopropanol not less than 1504kg, cooling and crystallizing all filtrate, carrying out centrifugal separation, washing with water and drying to obtain a pure product florfenicol, and mechanically hydrolyzing a crystallization mother liquor in the next batch. The final yield of this example was about 66.94562% as D ethyl ester.

Preferably, all of the foregoing reagents are chemically pure or purer. The water is deionized water, preferably double distilled water. The dosage proportion selection is data produced by industrial large-scale production, and in actual preparation, the actual preparation can be reduced by one to three orders of magnitude, and if kg is replaced by g, the situation still holds.

Since florfenicol is a mature product, no characterization data are given here, but the present application characterizes it, and the nuclear magnetic data are substantially consistent with other data in the prior art, which can confirm that florfenicol is prepared.

The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that are not thought of through the inventive work should be included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope defined by the claims.

Claims (4)

1. The utility model provides a preparation florfenicol's reinforced auxiliary device which characterized in that:

comprises a reduction reaction kettle (1), an air inlet part (2), an air outlet part (3), a funnel part (4), a cross rod part (5), an ultrasonic device (6), a left supporting part (7) and a right supporting part (8);

the reduction reaction kettle (1) is provided with an upper opening (11), an air inlet (12), an air outlet (13), a feed inlet (14) and a stirrer (15), wherein the upper opening (11), the air inlet (12), the air outlet (13) and the feed inlet (14) are respectively matched with an upper opening cover (111), an air inlet cover (121), an air outlet cover (131) and a feed inlet cover (141); the upper opening (11) is positioned right above the reduction reaction kettle, the air inlet (12) and the feed inlet (14) are positioned on the inclined plane on the right side of the upper opening (11), the air outlet (13) is positioned on the inclined plane on the left side of the upper opening (11), and the axis of the feed inlet (14) is parallel to the axis of the reduction reaction kettle;

the air inlet part (2) is provided with an air inlet pipe (21), an air inlet pump (22), an air inlet glass pipe (23), an air inlet plug (24) and a first fixing part (241); the air inlet pipe is made of polyester materials, the tail end of the air inlet pipe (21) is tightly sleeved at the outer end of the air inlet glass pipe (23), the air inlet glass pipe (23) is inserted into a through hole in the center of the air inlet plug (24) and is clamped by a first fixing part (241) tightly attached to the inner side of the through hole, and the inner end of the air inlet glass pipe (23) is provided with a bent hook part (231);

the air outlet part (3) is provided with an air outlet pipe (31), an air outlet pump (32), an air outlet glass tube (33), an air outlet plug (34) and a second fixing part (341); the air outlet pipe (31) is made of polyester materials, the tail end of the air outlet pipe (31) is tightly sleeved at the outer end of the air outlet glass pipe (33), the air outlet glass pipe (33) is divided into a thin part (333), a large-diameter part (331) and a horn part (332) from outside to inside, the thin part (333) is inserted into a through hole in the center of the air outlet plug (34), and the through hole is tightly clamped by a second fixing part (341) tightly attached to the inner side of the through hole;

the funnel part (4) is provided with a sealing ring (41), a body part (42), a lower leakage part (43), a wide mouth (44), a convex rod (45), a support edge (46) and a leakage net (47); the sealing ring (41) is made of silicon rubber and is provided with a horizontal ring part, an inner cylindrical layer and an outer cylindrical layer, the upper edges of the inner cylindrical layer and the outer cylindrical layer are connected with the ring part, a through hole is formed in the middle of the ring part, the part connected with the through hole is thickened, the outer diameter of the body part is matched with the through hole in the middle of the ring part, the lower leakage part (43) has an inner diameter not less than 1cm, a wide opening (44) is connected above the body part (42), a horizontal protruding rod (45) in welded connection is arranged on the right side of the body part (42) below the wide opening (44), a circle of supporting edge (46) protruding outwards is arranged on the outer side of the body part below the protruding rod (45), and a leakage net (47) made of woven steel wires is arranged inside the body part (42);

the cross rod part (5) is provided with a circular ring part (51), a left cross rod (52), a right cross rod (53) and a lining layer (54); the middle of the transverse rod part (5) is provided with a circular ring part (51), a lining (54) is pasted on the inner side of the circular ring part (51), the inner diameter of the circular ring part (51) is matched with the outer diameter of the body part (42), the supporting edge (46) is supported by the upper edge of the circular ring part (42), and the left side and the right side of the circular ring part (51) are respectively connected with a left cylindrical transverse rod (52) and a right cylindrical transverse rod (53) in a welding mode;

the ultrasonic device (6) is provided with a vibration head (61), a transducer (62), a generator (63), a power supply (64) and a cable (65), the vibration head (61) is connected with the transducer (62) through the cable (65), a connecting line of the vibration head (61) and the transducer (62) is wrapped in the reinforced cable (65), the transducer (62) is connected with the generator (63), and the generator (63) is powered by the power supply (64); the convex rod (45) is inserted into the groove in the vibration head (61) and is fixed by a plurality of groove screws (36);

the left support part (7) is provided with a left rod (71), a left base (72), a left cylinder (73), a left shock absorber (74) and a left center hole (741); the left supporting part (7) is positioned on the left side of the funnel part (4), the left base (72) is a cylindrical base with a screw hole in the middle, the lower end of a left rod (71) is screwed into the screw hole to be fixed, the upper end of the left rod (71) is connected with a left cylinder (73) in a welding mode, the left cylinder is a hollow cylinder with a horizontal axis, the left shock absorber (74) is a polyurethane elastomer bonded in the left cylinder (73), and a left central hole (741) which is horizontal and suitable for the left cross rod (52) to be inserted and fixed is arranged in the center of the left shock absorber (74);

the right support part (8) is provided with a right rod (81), a right base (82), a right cylinder (83), a right shock absorber (84) and a right center hole (841); the right supporting part (8) is positioned at the right side of the funnel part (4), the right base (82) is a cylindrical base with a screw hole in the middle, the lower end of a right rod (81) is screwed into the screw hole to be fixed, the upper end of the right rod (81) is welded and connected with a right cylinder (83), the right cylinder is a hollow cylinder with a horizontal axis, the right shock absorber (84) is a polyurethane elastomer bonded in the right cylinder (83), and the center of the right shock absorber (84) is provided with a right center hole (841) which is horizontal and suitable for the right cross rod (53) to be inserted and fixed;

the center of the lower part of the reduction reaction kettle (1) is provided with a stirrer which extends inwards.

2. A feeding aid for the preparation of florfenicol as set forth in claim 1, wherein:

the upper opening (11), the air inlet (12), the air outlet (13), the feed inlet (14) and the corresponding upper opening cover (111), the air inlet cover (121), the air outlet cover (131) and the feed inlet cover (141) are fastened or screwed;

the flow rates of the air inlet pump (22) and the air outlet pump (32) are controlled to be 1-2L/min;

the first fixing part (241) and the second fixing part (341) are made of a polyurethane material gasket;

the average pore diameter of the screen (47) is slightly larger than that of a 20-mesh screen;

the air inlet glass tube (23) and the air outlet glass tube (33) are made of transparent and corrosion-resistant glass;

the upper cover (111), the air inlet cover (121), the air outlet cover (131), the charging cover (141), the air inlet plug (24) and the air outlet plug (34) are made of any one of nylon PA66, polytetrafluoroethylene or engineering plastic materials;

the working frequency of the vibration head is between 15KHZ and 100 KHZ;

the cross rod part (5), the left support part (7) and the right support part (8) are made of stainless steel;

the polyurethane elastomer has a Shore D hardness of 50 or more.

3. A process for the preparation of florfenicol using the feed assist device of any of claims 1-2, comprising the steps of;

(1) installing and trial run: taking down an upper opening cover, an air inlet cover and an air outlet cover of a reduction reaction kettle, respectively installing an air inlet plug and an air outlet plug, installing an air inlet glass tube (23) and an air outlet glass tube (33) from the opened upper opening, respectively connecting an air inlet tube (21), an air inlet pump (22), an air outlet tube (31) and an air outlet pump (32), covering the upper opening cover (111), introducing nitrogen at the speed of 1-2L/min by using an air inlet part, leading out gas at the same speed by using the air outlet part, and repeatedly opening and closing the upper opening until the opening and closing do not cause obvious change of air pressure;

(2) a funnel part mounting step: the left supporting part and the right supporting part are arranged in front of and behind the funnel part, the charging port cover is removed and replaced by a sealing ring, the sealing ring is tightly sleeved on the charging port, the circular ring part (51) is positioned right above the axis of the sealing ring, the funnel is inserted into the circular ring part, so that the supporting edge (46) is attached to the circular ring part (51), the convex rod (45) is inserted into a groove in the vibrating head (61), and the convex rod is fixed by a plurality of groove screws (36); the lower part of the body part adjacent to the circular part (51) is wound and fixed by electrical tape for a plurality of circles;

(3) a reduction reaction step: putting D-p-methylsulfonylphenylserine ethyl ester and methanol into a reduction reaction kettle, stirring to dissolve the D-p-methylsulfonylphenylserine ethyl ester and the methanol, grinding potassium borocyanide to an average particle size of about 40 meshes, putting the ground potassium borocyanide into a funnel in batches, introducing nitrogen into an air inlet part at a speed of 1-2L/min, introducing gas out of an air outlet part at the same speed, controlling the reaction temperature to be not more than 30 ℃ by using jacket brine ice, continuing the process until the potassium borocyanide is added completely, removing the jacket brine ice after the potassium borohydride is completely added, naturally heating the system, introducing a little steam, continuously introducing nitrogen, controlling the temperature in the reaction kettle to be 60 ℃, and keeping the temperature for 5-7 hours; then evaporating most of methanol by decompression to obtain a reaction mixture in the third step;

(4) a cyclization reaction step: transferring the reaction mixture obtained in the third step to a cyclization reaction kettle, cooling, adding glycerol into the reaction kettle, continuously distilling out most of the residual methanol under normal pressure, cooling the reaction mixture to about 40 ℃, dropwise adding glacial acetic acid, stirring for one hour after dropwise adding, continuously dropwise adding dichloroacetonitrile, heating to 55 ℃ after the dropwise adding is finished, keeping the temperature until solids are separated out, continuously preserving the temperature for 16-20 hours, adding water into the reaction mixture to separate out a large amount of solids, cooling to 15-25 ℃, performing centrifugal separation, and drying to obtain a cyclic compound intermediate;

(5) a fluorinating agent preparation step: setting a fluorinating agent preparation kettle, adding dichloromethane and diethylamine into the kettle, introducing liquid nitrogen, cooling to below-30 ℃, starting introducing hexafluoropropylene, and stirring and keeping the current temperature for 1-2 hours after a preset amount of hexafluoropropylene is introduced to obtain an Ishikawa fluorinating agent;

(6) a fluorination reaction step: setting a fluorination reaction kettle, weighing a dry cyclic compound intermediate, adding the dry cyclic compound intermediate into the fluorination reaction kettle, adding dichloromethane, stirring for dissolving, pumping an Ishikawa fluorination reagent into the fluorination reaction kettle, opening a jacket of the fluorination reaction kettle, heating by steam, controlling the reaction temperature to be 85-95 ℃, pressurizing to 4-5 atmospheric pressures in the kettle, carrying out heat preservation and pressure maintaining reaction for 2 hours, cooling to 25-35 ℃, and transferring all reaction mixtures into a hydrolysis kettle;

(7) a hydrolysis reaction step: adding water and sodium acetate into a reaction mixture in a hydrolysis kettle, heating and distilling to evaporate dichloromethane, adding the previous batch of crystallization mother liquor obtained in the step (8) after the dichloromethane is evaporated, continuously heating to 75-85 ℃, reacting for 4 hours, continuously evaporating isopropanol and water after the reaction is finished until most of the isopropanol is evaporated to obtain a viscous mixture, cooling, and performing centrifugal separation to obtain a crude florfenicol product;

(8) refining: taking a refining kettle for standby, adding a florfenicol crude product into a mixed solution of isopropanol and water in the refining kettle, heating until the crude product starts to be dissolved, keeping the current temperature for 30-60min, adding activated carbon for decolorization, filtering out waste activated carbon, cooling and crystallizing all filtrate, performing centrifugal separation, washing with water and drying to obtain a pure florfenicol product, and mechanically hydrolyzing a crystallization mother liquor in the next batch.

4. A process for the preparation of florfenicol as claimed in claim 3 comprising the steps of;

(1) installing and trial run: taking down an upper opening cover, an air inlet cover and an air outlet cover of a reduction reaction kettle, respectively installing an air inlet plug and an air outlet plug, installing an air inlet glass tube (23) and an air outlet glass tube (33) from the opened upper opening, respectively connecting an air inlet tube (21), an air inlet pump (22), an air outlet tube (31) and an air outlet pump (32), covering the upper opening cover (111), introducing nitrogen at the speed of 1.4-1.6L/min by using an air inlet part, leading out gas at the same speed by using the air outlet part, and repeatedly opening and closing the upper opening until the opening and closing can not cause obvious change of air pressure;

(2) a funnel part mounting step: the left supporting part and the right supporting part are arranged in front of and behind the funnel part, the charging port cover is removed and replaced by a sealing ring, the sealing ring is tightly sleeved on the charging port, the circular ring part (51) is positioned right above the axis of the sealing ring, the funnel is inserted into the circular ring part, so that the supporting edge (46) is attached to the circular ring part (51), the convex rod (45) is inserted into a groove in the vibrating head (61), and the convex rod is fixed by a plurality of groove screws (36); the lower part of the body part adjacent to the circular part (51) is wound and fixed by electrical tape for a plurality of circles;

(3) a reduction reaction step: putting D-p-methylsulfonylphenylserine ethyl ester and methanol into a reduction reaction kettle, stirring to dissolve the D-p-methylsulfonylphenylserine ethyl ester and the methanol, grinding potassium borocyanide to an average particle size of about 40 meshes, putting the ground potassium borocyanide into a funnel in batches, introducing nitrogen at the speed of 1.4-1.6L/min of an air inlet part, introducing gas at the same speed of an air outlet part, controlling the reaction temperature to be not more than 30 ℃ by using jacket ice salt water, continuing the process until the potassium borocyanide is added completely, removing the jacket ice salt water after the potassium borohydride is completely added, naturally heating the system, introducing a little steam, continuously introducing nitrogen, controlling the temperature in the reaction kettle to be 60 ℃, and keeping the temperature for 6 hours; then evaporating most of methanol by decompression to obtain a reaction mixture in the third step;

(4) a cyclization reaction step: transferring the reaction mixture obtained in the third step to a cyclization reaction kettle, cooling, adding glycerol into the reaction kettle, continuously distilling out most of the residual methanol under normal pressure, cooling the reaction mixture to about 40 ℃, dropwise adding glacial acetic acid, stirring for one hour after dropwise adding, continuously dropwise adding dichloroacetonitrile, heating to 55 ℃ after completing addition, keeping the temperature until solids are separated out, continuously preserving heat for 18 hours, adding water into the reaction mixture to separate out a large amount of solids, cooling to 20 ℃, performing centrifugal separation, and drying to obtain a cyclic compound intermediate;

(5) a fluorinating agent preparation step: setting a fluorinating agent preparation kettle, adding dichloromethane and diethylamine into the kettle, introducing liquid nitrogen, cooling to below-30 ℃, starting introducing hexafluoropropylene, and stirring and keeping the current temperature for 1.5 hours after a preset amount of hexafluoropropylene is introduced to obtain an Ishikawa fluorinating agent;

(6) a fluorination reaction step: setting a fluorination reaction kettle, weighing a dry cyclic compound intermediate, adding the cyclic compound intermediate into the fluorination reaction kettle, adding dichloromethane, stirring for dissolving, pumping an Ishikawa fluorination reagent into the fluorination reaction kettle, opening a jacket of the fluorination reaction kettle, heating by steam, controlling the reaction temperature to be 90 ℃, pressurizing to 4.5 atmospheric pressure in the kettle, carrying out heat preservation and pressure maintaining reaction for 2 hours, cooling to 30 ℃, and transferring all reaction mixtures into a hydrolysis kettle;

(7) a hydrolysis reaction step: adding water and sodium acetate into a reaction mixture in a hydrolysis kettle, heating and distilling to evaporate dichloromethane, adding the last batch of crystallization mother liquor obtained in the step (8) after the dichloromethane is evaporated, continuously heating to 80 ℃, reacting for 4 hours, continuously evaporating isopropanol and water after the reaction is finished until most of the isopropanol is evaporated to obtain a viscous mixture, cooling, and performing centrifugal separation to obtain a crude florfenicol product;

(8) refining: taking a refining kettle for standby, adding a florfenicol crude product into a mixed solution of isopropanol and water in the refining kettle, heating until the crude product starts to be dissolved, keeping the current temperature for 50min, adding activated carbon for decolorization, filtering out waste activated carbon, cooling and crystallizing all filtrate, carrying out centrifugal separation, washing with water and drying to obtain a pure florfenicol product, and mechanically hydrolyzing a crystallization mother liquor in the next batch.

Images