CN112645965B - Preparation process of ceftiofur sodium for vacuum freeze-drying injection - Google Patents
Preparation process of ceftiofur sodium for vacuum freeze-drying injection Download PDFInfo
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- CN112645965B CN112645965B CN202011529299.1A CN202011529299A CN112645965B CN 112645965 B CN112645965 B CN 112645965B CN 202011529299 A CN202011529299 A CN 202011529299A CN 112645965 B CN112645965 B CN 112645965B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B02—CRUSHING, PULVERISING, OR DISINTEGRATING; PREPARATORY TREATMENT OF GRAIN FOR MILLING
- B02C—CRUSHING, PULVERISING, OR DISINTEGRATING IN GENERAL; MILLING GRAIN
- B02C2/00—Crushing or disintegrating by gyratory or cone crushers
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B02—CRUSHING, PULVERISING, OR DISINTEGRATING; PREPARATORY TREATMENT OF GRAIN FOR MILLING
- B02C—CRUSHING, PULVERISING, OR DISINTEGRATING IN GENERAL; MILLING GRAIN
- B02C2/00—Crushing or disintegrating by gyratory or cone crushers
- B02C2/007—Feeding devices
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B02—CRUSHING, PULVERISING, OR DISINTEGRATING; PREPARATORY TREATMENT OF GRAIN FOR MILLING
- B02C—CRUSHING, PULVERISING, OR DISINTEGRATING IN GENERAL; MILLING GRAIN
- B02C23/00—Auxiliary methods or auxiliary devices or accessories specially adapted for crushing or disintegrating not provided for in preceding groups or not specially adapted to apparatus covered by a single preceding group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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Abstract
The invention discloses a preparation process of ceftiofur sodium for vacuum freeze-drying injection, which comprises the following steps: instrument and reagent preparation: preparing an element analyzer, an infrared spectrometer, a nuclear magnetic resonance spectrometer and a mass spectrometer, preparing a commercially available AR-grade reagent, and detecting the reagent (II): detecting and analyzing the prepared reagent by an element analyzer, an infrared spectrometer, a nuclear magnetic resonance spectrometer and a mass spectrometer, and recording related data, (III) preparing 2-furanmethanethiol: adding 500 ml-700 ml of ethanol, 30 ml-40 ml of water and 35 g-45 g of NaHS into a reagent bottle, and dropwise adding 30 g-40 g of 2-furoyl chloride at the temperature of 24-28 ℃ while stirring. The preparation process of ceftiofur sodium for vacuum freeze-drying injection utilizes the following steps of 1: 1, the active carbon and the adsorption resin are combined with a filtering and recrystallization mode, so that oil products can be effectively removed, and the purity of the ceftiofur sodium in the subsequent preparation is improved.
Description
Technical Field
The invention relates to the technical field of ceftiofur sodium preparation, in particular to a preparation process of ceftiofur sodium for vacuum freeze-drying injection.
Background
Ceftiofur sodium is white powder insoluble in water, is a cephalosporium antibiotic specially used for animals in the third generation, has an ultra-broad-spectrum and strong antibacterial action and strong antibacterial activity, has a good inhibition effect on gram-positive bacteria and gram-negative bacteria, has low toxicity and high safety, does not have adverse effect on most animals, and needs to be improved and perfected along with the wide use of ceftiofur sodium in the animal husbandry industry, but the existing preparation process of ceftiofur sodium for vacuum freeze-drying injection still has the following problems;
1. in the process of preparing ceftiofur sodium, a large amount of dispersing agents and other substances are used, so that irritation is easily caused to skin eyes and the like, and the use of ceftiofur sodium is limited;
2. in the conventional preparation process of ceftiofur sodium for vacuum freeze-drying injection, other impurities are contained in ceftiofur sodium in the preparation process of ceftiofur sodium, the quality is uneven, and the production quality cannot be guaranteed, so that the use effect of the subsequent ceftiofur sodium is influenced, for example, in the application number CN201510707395.3, the preparation process of ceftiofur sodium for injection is prevented from being unloaded, although the problem that ceftiofur sodium cannot effectively control the product in the preparation process is well solved, the problem that the performance of ceftiofur sodium is unstable due to long-term storage is not solved
Therefore, we propose a process for preparing ceftiofur sodium for injection by vacuum freeze-drying, so as to solve the problems mentioned above.
Disclosure of Invention
The invention aims to provide a preparation process of ceftiofur sodium for vacuum freeze-drying injection, so as to solve the problems that the preparation process of ceftiofur sodium for vacuum freeze-drying injection in the current market is complicated, the time consumption is long, the production efficiency is low, and the market demand of ceftiofur sodium cannot be met, and meanwhile, in the preparation process of the conventional ceftiofur sodium for vacuum freeze-drying injection, other impurities are contained in the ceftiofur sodium, the quality is uneven, the production quality cannot be guaranteed, and the subsequent extraction work of the using effect of ceftiofur sodium is influenced.
In order to achieve the purpose, the invention provides the following technical scheme: a preparation process of ceftiofur sodium for vacuum freeze-drying injection comprises the following steps:
instrument and reagent preparation: preparing an element analyzer, an infrared spectrometer, a nuclear magnetic resonance spectrometer and a mass spectrometer, and preparing a commercially available AR-grade reagent;
(II) reagent detection: detecting and analyzing the prepared reagent by an element analyzer, an infrared spectrometer, a nuclear magnetic resonance spectrometer and a mass spectrometer, and recording related data;
(III) preparing 2-furanmethylthiohydroxy acid: adding 500-700 ml of ethanol, 30-40 ml of water and 35-45 g of NaHS into a reagent bottle, dropwise adding 30-40 g of 2-furoyl chloride while stirring at the temperature of 24-28 ℃, reacting for 1-1.5 h, evaporating to remove the ethanol, adding 2000-2500 ml of water, adjusting the pH value of the solution to acidity, and drying after extraction;
(IV) preparing an intermediate: adding 600 ml-800 ml of water and 30 g-40 g of Na into a reagent bottle2CO3Then adding 35g to 45g of 7-ACA and 2-furanmethanethiol, uniformly stirring, adjusting the pH of the solution to be neutral, and adding N2Under the protection of (1), heating to 40-60 ℃ for reaction for 2-2.5 h, cooling to 22-28 ℃ for filtration and water washing, and then drying under reduced pressure at 20-40 ℃ to obtain an intermediate;
(V) preparing ceftiofur acid: adding 12g to 15g of intermediate, 20g to 30g of AE active ester, 20g to 30g of triethylamine and 120ml to 150ml of dichloromethane into a reagent bottle, reacting for 3.5h to 4h at 42 ℃ to 52 ℃, cooling to 24 ℃ to 28 ℃, extracting for three times by using 60ml to 100ml of water respectively, and combining water layers;
(VI) decoloring treatment: decolorizing ceftiofur acid by using a decolorizing agent, adjusting the pH value to acidity after decolorizing, filtering, drying under reduced pressure at the temperature of 20-30 ℃ to obtain a crude product, and purifying the crude product by recrystallization;
(seventhly) preparing ceftiofur hydrochloride: adding 80-100 mL of acetone, 4-8 mL of water and 8-12 g of ceftiofur acid into a reagent bottle, then adding 2-5 mL of concentrated hydrochloric acid while stirring, supplementing 80-100 mL of acetone after ceftiofur hydrochloride begins to crystallize, continuing stirring for 20-40 min, filtering, washing with a small amount of acetone, and drying under reduced pressure at 20-24 ℃ to obtain ceftiofur hydrochloride;
(eighth) preparation of solution one: mixing 8 g-10 g of ceftiofur hydrochloride, a dispersing agent, 80 ml-100 ml of tetrahydrofuran and 8 ml-12 ml of water, stirring for 0.5 h-1 h, and filtering to obtain a solution I;
(nine) preparation of solution two: stirring a mixed solution prepared from a salt forming agent, 2-4 g of NaOH and 100-150 ml of tetrahydrofuran for 0.5-1 h to prepare a solution II;
(tenth) preparation of ceftiofur sodium: dripping the solution into the second solution, stirring for 30-50 min, filtering, washing with acetone, and drying to obtain ceftiofur sodium salt;
(eleven) grinding: grinding the dried ceftiofur sodium salt into powder;
(twelve) bottling: quantitatively filling ceftiofur sodium powder into a clean reagent bottle according to the specification, and labeling and packaging the sealed reagent bottle;
(thirteen) preservation: and (4) storing the tested ceftiofur sodium vacuum freeze-dried injection in a dry and dark place.
Preferably, in the process of preparing the 2-furanmethanethiol in the step (three), the pH of the solution is adjusted to be acidic by 3-6 mol/L of HCL, which is beneficial to increasing the adjustment speed of the pH, in the process of extracting the solution, 100-200 ml of ethyl acetate is respectively used for extraction for 5-7 times, and the ethyl acetate layers are combined.
Preferably, the step (six) is to mix the activated carbon and the adsorption resin 1: 1, removing impurities and oxides in the oil product, and performing recrystallization by using a mass ratio of ethanol to acetone of 2: 1 as a solvent.
Preferably, in the step (eight), polyvinylpyrrolidone is used as a dispersing agent and also used as a cryopreservative agent in the process of preparing the solution one, and the polyvinylpyrrolidone does not cause any irritation to skin, mucous membrane, eye and the like and has excellent physiological inertness.
Preferably, in the step (nine), isooctanoic acid is used as a salt forming agent in the process of preparing the solution II, and the isooctanoic acid has excellent chemical stability.
Preferably, in the step (ten), in the process of preparing ceftiofur sodium, the mixed solution is dried by reduced pressure drying at the temperature of 45-50 ℃ and under the pressure of 2.0-2.5 kPa.
Preferably, the milling device used for milling the powder in the eleventh step comprises supporting legs, a fixing plate, a fixing tube, a hopper, a power mechanism and a movable milling block, wherein the top ends of the plurality of groups of supporting legs are connected with the bottom end of the fixing plate, the fixing tube is installed on the fixing plate, the hopper is installed at the input end of the fixing tube, the top end of the fixing plate is provided with an inclined block, the heights of the inclined blocks are sequentially reduced from right to left, the left end of the fixing tube is communicated with a discharge hole, the fixing tube is fixedly sleeved with the inclined block, the power mechanism is installed at the bottom end of the fixing plate, the output end of the power mechanism penetrates through the bottom ends of the fixing plate and the inclined block respectively and is connected with the input end of the movable milling block, and the fixed tube is internally provided with the static milling block; the device also comprises a connecting plate, a fixed block, a first spring, sliding plates, limit blocks, a push rod and a second spring, wherein a round hole is arranged at the top end of the connecting plate, the output end of the round hole is connected with the input end of a fixed pipe, a round groove is arranged in the central area of the bottom end of the fixed block, a through hole is communicated with the inner side wall of the round groove, the input end of the through hole is connected with the output end of a hopper, the through hole is arranged above the round hole, the top end of the connecting plate is contacted with the bottom end of the fixed block, mounting grooves are symmetrically arranged at the left end and the right end of the connecting plate, fixing grooves are communicated with the inner ends of the two sets of mounting grooves, two sets of first springs are respectively mounted in the fixing grooves, the outer ends of the two sets of first springs are respectively connected with the inner ends of the two sets of sliding plates, the two sets of limit blocks are respectively connected with the outer ends of the two sets of sliding plates, arc grooves are symmetrically arranged on the left side wall and the inner right side wall of the round groove, and the outer ends of the two sets of limit blocks are respectively inserted into the two sets of arc grooves, two sets of arc walls all communicate and are provided with the handle hole, and two sets of handle holes all communicate and are provided with the spout, and two sets of push rods all are provided with the limiting plate with two sets of handle hole slip suit respectively on two sets of push rods, two sets of limiting plates respectively with two sets of spout slip suit, on two sets of second springs on the suit respectively two sets of push rods, two sets of push pedals are installed respectively in two sets of push rod outer ends.
The grinding device further comprises a horizontal plate, third springs, movable plates and ejector blocks, wherein a fixing hole is formed in the central area of the top end of the horizontal plate, a fixing pipe is fixedly sleeved with the fixing hole, two groups of square grooves are symmetrically formed in the top end of the horizontal plate, spring grooves are formed in the bottom ends of the two groups of square grooves in a communicated mode, the two groups of third springs are installed in the two groups of spring grooves respectively, the two groups of movable plates are in sliding contact with the two groups of spring grooves respectively, the bottom ends of the two groups of movable plates are connected with the top ends of the two groups of third springs respectively, the two groups of ejector blocks are in sliding contact with the two groups of square grooves respectively, the bottom ends of the two groups of ejector blocks are connected with the top ends of the two groups of movable plates respectively, and the top ends of the two groups of ejector blocks are in contact with the bottom ends of the fixing block.
According to the milling device, the sealing gasket is arranged on the connecting plate.
The milling device further comprises a guide pipe, wherein the input end of the guide pipe is connected with the output end of the discharge hole, and the output end of the guide pipe penetrates through the left half area of the top end of the fixing plate.
The grinding device further comprises a cover plate, a hinge and a handle, wherein the lower half area of the right end of the cover plate is hinged with the upper half area of the right end of the hopper through the hinge, and the handle is installed on the cover plate.
According to the milling device, the hopper is provided with the transparent plate.
According to the milling device, the handle is provided with the handle sleeve.
The milling device further comprises ground feet, and the multiple groups of ground feet are respectively installed at the bottom ends of the multiple groups of supporting legs.
Compared with the prior art, the invention has the beneficial effects that: through setting up the connecting plate, operating personnel inwards presses simultaneously and moves two sets of push pedals, two sets of push pedals respectively with two sets of push rod cooperations respectively at the spacing downstream inward movement of two sets of handle holes, continue to press down the fixed block after butt joint connecting plate and circular slot, two sets of push rod inner contacts with two sets of stopper outer ends respectively, continue inwards to press and move the push pedal, two sets of stoppers watch on and push the back and get into the mounting groove, push down to the fixed block bottom and the back of connecting plate top end, loosen two sets of push pedals, two sets of first springs promote two sets of stoppers respectively with two sets of slide cooperations and get into two sets of arcs respectively, fix connecting plate and fixed block, press two sets of push pedals simultaneously during the dismantlement, upwards mention the fixed block can, be convenient for change the accessory and maintain the grinding region of device, the practicality of device is improved.
Compared with the prior art, the invention has the beneficial effects that: according to the preparation process of ceftiofur sodium for vacuum freeze-drying injection, in the process of preparing ceftiofur sodium, polyvinylpyrrolidone is used as a dispersing agent and also used as a low-temperature preservative, the polyvinylpyrrolidone has excellent physiological inertia, and does not cause any stimulation to skin, mucous membranes, eyes and the like, so that the application range of ceftiofur sodium can be effectively enlarged;
(1) during the decoloring treatment, the activated carbon and the adsorbent resin 1: 1, removing impurities and oxides in the oil product, and performing recrystallization by using a mass ratio of ethanol to acetone of 2: 1 as a solvent, using a mixture of 1: 1, the active carbon and the adsorption resin are combined with a filtering and recrystallization mode to effectively remove impurities in the oil product, and in addition, the impurity removal, the odor removal, the decoloration and the separation are integrated, so that the oil product is changed into light-colored transparent liquid, the purity of the subsequent preparation of ceftiofur sodium is improved, and the subsequent use effect of the ceftiofur sodium is favorably improved;
(2) in the process of preparing ceftiofur sodium, the mixed solution is dried under reduced pressure at the temperature of 45 ℃ and the pressure of 2.0kPa, the drying time can be effectively shortened, and the contact area of the materials and air is reduced, so that the adverse effect of the air on the product is reduced, and the dried product is in a crisp sponge shape, is loose and easy to crush and is beneficial to subsequent grinding.
Drawings
FIG. 1 is a schematic structural view of the present invention;
FIG. 2 is an enlarged schematic view of portion A of FIG. 1;
FIG. 3 is a schematic view of the connection structure of the hopper and the power mechanism in the present invention;
FIG. 4 is a front view of the present invention;
in the drawings, the reference numbers: 1. a support leg; 2. a fixing plate; 3. a fixed tube; 4. a hopper; 5. a sloping block; 6. a power mechanism; 7. moving the grinding block; 8. a static grinding block; 9. a connecting plate; 10. a fixed block; 11. a first spring; 12. a slide plate; 13. a limiting block; 14. a push rod; 15. a limiting plate; 16. a second spring; 17. a horizontal plate; 18. a third spring; 19. a movable plate; 20. a top block; 21. a gasket; 22. a conduit; 23. a cover plate; 24. a hinge; 25. a handle; 26. a transparent plate; 27. covering the handlebar; 28. and (5) ground feet.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and 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 invention.
The first embodiment is as follows:
a preparation process of ceftiofur sodium for vacuum freeze-drying injection comprises the following steps of:
instrument and reagent preparation: preparing an element analyzer, an infrared spectrometer, a nuclear magnetic resonance spectrometer and a mass spectrometer, and preparing a commercially available AR-grade reagent;
(II) reagent detection: detecting and analyzing the prepared reagent by an element analyzer, an infrared spectrometer, a nuclear magnetic resonance spectrometer and a mass spectrometer, and recording related data;
(III) preparing 2-furanmethylthiohydroxy acid: adding 500ml of ethanol, 30ml of water and 35g of NaHS into a reagent bottle, dropwise adding 30g of 2-furoyl chloride while stirring at the temperature of 24 ℃, then reacting for 1h, evaporating the ethanol, adding 2000ml of water, adjusting the pH of the solution to acidity, and drying after extraction;
(IV) preparing an intermediate: to the reagent bottle, 600ml of water and 30g of Na were added2CO3Then 35g of 7-ACA and 2-furanmethanethiol are added, the solution is stirred evenly, the pH value of the solution is adjusted to be neutral, and the solution is added with N2Under the protection of (3), heating to 40 ℃ for reaction for 2h, then cooling to 22 ℃ for filtration and water washing, and then drying under reduced pressure at 20 ℃ to obtain an intermediate;
(V) preparing ceftiofur acid: adding 12g of intermediate, 20g of AE active ester, 20g of triethylamine and 120ml of dichloromethane into a reagent bottle, reacting for 3.5h at 42 ℃, cooling to 24 ℃, extracting with 60ml of water for three times respectively, and combining water layers;
(VI) decoloring treatment: decolorizing ceftiofur acid with decolorizing agent, adjusting pH to acidity after decolorizing, filtering, drying under reduced pressure at 20 deg.C to obtain crude product, and purifying the crude product by recrystallization;
(seventhly) preparing ceftiofur hydrochloride: adding 80mL of acetone, 4mL of water and 8g of ceftiofur acid into a reagent bottle, then adding 2mL of concentrated hydrochloric acid while stirring, supplementing 80mL of acetone after ceftiofur hydrochloride begins to crystallize out, continuing stirring for 20min, filtering, washing a small amount of acetone, and drying under reduced pressure at 20 ℃ to obtain ceftiofur hydrochloride;
(eighth) preparation of solution one: mixing 8g of ceftiofur hydrochloride, a dispersing agent, 80ml of tetrahydrofuran and 8ml of water, stirring for 0.5h, and filtering to obtain a solution I;
(nine) preparation of solution two: stirring a mixed solution prepared from a salt forming agent, 2g of NaOH and 100ml of tetrahydrofuran for 0.5h to prepare a solution II;
(tenth) preparation of ceftiofur sodium: adding the solution into the solution II one drop by one drop, stirring for 30min, filtering, washing with acetone, and drying to obtain ceftiofur sodium salt;
(eleven) grinding: grinding the dried ceftiofur sodium salt into powder;
(twelve) bottling: quantitatively filling ceftiofur sodium powder into a clean reagent bottle according to the specification, and labeling and packaging the sealed reagent bottle;
(thirteen) preservation: the tested ceftiofur sodium vacuum freeze-dried injection is placed in a dry and dark place to be stored for 4 months.
And (3) in the process of preparing the 2-furanmethanethiol through the step (three), adjusting the pH of the solution to acidity through 3mol/L HCL, facilitating the improvement of the pH adjusting speed, extracting the solution for 5 times by using 100ml of ethyl alcohol respectively in the process of extracting the solution, and combining ethyl acetate layers.
Step (six) in the process of decoloring, mixing the activated carbon and the adsorption resin 1: 1, removing impurities and oxides in the oil product, and performing recrystallization by using a mass ratio of ethanol to acetone of 2: 1 as a solvent.
And (VIII) in the process of preparing the solution I, polyvinylpyrrolidone is used as a dispersing agent and is also used as a low-temperature preservative, and the polyvinylpyrrolidone does not cause any stimulation to skin, mucous membranes, eyes and the like and has excellent physiological inertia.
In the process of preparing the solution II, the isooctanoic acid is used as a salt forming agent, and the isooctanoic acid has excellent chemical stability.
And (ten) drying the mixed solution by reduced pressure drying at the temperature of 45 ℃ and the pressure of 2.0kPa in the process of preparing the ceftiofur sodium.
Example two:
a preparation process of ceftiofur sodium for vacuum freeze-drying injection comprises the following steps of:
instrument and reagent preparation: preparing an element analyzer, an infrared spectrometer, a nuclear magnetic resonance spectrometer and a mass spectrometer, and preparing a commercially available AR-grade reagent;
(II) reagent detection: detecting and analyzing the prepared reagent by an element analyzer, an infrared spectrometer, a nuclear magnetic resonance spectrometer and a mass spectrometer, and recording related data;
(III) preparing 2-furanmethylthiohydroxy acid: adding 600ml of ethanol, 33ml of water and 33g of NaHS into a reagent bottle, dropwise adding 33g of 2-furoyl chloride while stirring at the temperature of 25 ℃, then reacting for 1.2h, evaporating the ethanol, adding 2200ml of water, adjusting the pH value of the solution to acidity, and performing drying treatment after extraction;
(IV) preparing an intermediate: 650ml of water and 33g of Na were added to the reagent bottle2CO3Then adding 33g of 7-ACA and 2-furanmethanethiol, stirring uniformly, adjusting the pH of the solution to be neutral, and adding N2Under the protection of (3), heating to 47 ℃ for reaction for 2.2h, cooling to 24 ℃ for filtration and water washing, and then drying under reduced pressure at 27 ℃ to obtain an intermediate;
(V) preparing ceftiofur acid: adding 13g of intermediate, 23g of AE active ester, 23g of triethylamine and 130ml of dichloromethane into a reagent bottle, reacting for 3.5h at 45 ℃, cooling to 26 ℃, extracting with 70ml of water for three times respectively, and combining water layers;
(VI) decoloring treatment: decolorizing ceftiofur acid with decolorizing agent, adjusting pH to acidity after decolorizing, filtering, drying under reduced pressure at 23 deg.C to obtain crude product, and purifying the crude product by recrystallization;
(seventhly) preparing ceftiofur hydrochloride: adding 87mL of acetone, 5mL of water and 9g of ceftiofur acid into a reagent bottle, then adding 3mL of concentrated hydrochloric acid while stirring, supplementing 87mL of acetone after ceftiofur hydrochloride begins to crystallize out, continuing stirring for 27min, filtering, washing with a small amount of acetone, and drying under reduced pressure at 22 ℃ to obtain ceftiofur hydrochloride;
(eighth) preparation of solution one: mixing 8.5g of ceftiofur hydrochloride, a dispersing agent, 87ml of tetrahydrofuran and 9ml of water, stirring for 0.6h, and filtering to obtain a solution I;
(nine) preparation of solution two: stirring a mixed solution prepared from a salt forming agent, 2.5g of NaOH and 110ml of tetrahydrofuran for 0.6h to prepare a solution II;
(tenth) preparation of ceftiofur sodium: adding the solution into the second solution one drop by one drop, stirring for 40min, filtering, washing with acetone, and drying to obtain ceftiofur sodium salt;
(eleven) grinding: grinding the dried ceftiofur sodium salt into powder;
(twelve) bottling: quantitatively filling ceftiofur sodium powder into a clean reagent bottle according to the specification, and labeling and packaging the sealed reagent bottle;
(thirteen) preservation: the tested ceftiofur sodium vacuum freeze-dried injection is placed in a dry and dark place to be stored for 8 months.
And (3) in the process of preparing the 2-furanmethanethiol through the step (three), adjusting the pH of the solution to be acidic through 4mol/L HCL, so as to be beneficial to improving the adjustment speed of the pH, extracting the solution for 5 times by using 130ml of ethyl alcohol respectively in the process of extracting the solution, and merging ethyl acetate layers.
Step (six) in the process of decoloring, mixing the activated carbon and the adsorption resin 1: 1, removing impurities and oxides in the oil product, and performing recrystallization by using a mass ratio of ethanol to acetone of 2: 1 as a solvent.
And (VIII) in the process of preparing the solution I, polyvinylpyrrolidone is used as a dispersing agent and is also used as a low-temperature preservative, and the polyvinylpyrrolidone does not cause any stimulation to skin, mucous membranes, eyes and the like and has excellent physiological inertia.
In the process of preparing the solution II, the isooctanoic acid is used as a salt forming agent, and the isooctanoic acid has excellent chemical stability.
And (ten) drying the mixed solution by reduced pressure drying at the temperature of 42 ℃ and under the pressure of 2.2kPa in the process of preparing the ceftiofur sodium.
Example three:
a preparation process of ceftiofur sodium for vacuum freeze-drying injection comprises the following steps of:
instrument and reagent preparation: preparing an element analyzer, an infrared spectrometer, a nuclear magnetic resonance spectrometer and a mass spectrometer, and preparing a commercially available AR-grade reagent;
(II) reagent detection: detecting and analyzing the prepared reagent by an element analyzer, an infrared spectrometer, a nuclear magnetic resonance spectrometer and a mass spectrometer, and recording related data;
(III) preparing 2-furanmethylthiohydroxy acid: adding 700ml of ethanol, 36ml of water and 41g of NaHS into a reagent bottle, dropwise adding 36g of 2-furoyl chloride while stirring at the temperature of 24 ℃, then reacting for 1.4h, evaporating the ethanol, adding 2400ml of water, adjusting the pH value of the solution to acidity, extracting and drying;
(IV) preparing an intermediate: to a reagent bottle, 700ml of water and 36g of Na were added2CO3Then 41g of 7-ACA and 2-furanmethanethiol are added, the solution is stirred evenly, the pH value is adjusted to be neutral, and the mixture is added in N2Under the protection of (1), heating to 46 ℃ for reaction for 2.4h, cooling to 26 ℃ for filtration and water washing, and then drying under reduced pressure at 34 ℃ to obtain an intermediate;
(V) preparing ceftiofur acid: adding 14g of the intermediate, 26g of AE active ester, 26g of triethylamine and 140ml of dichloromethane into a reagent bottle, reacting for 3.9h at 48 ℃, cooling to 27 ℃, extracting with 80ml of water for three times respectively, and combining water layers;
(VI) decoloring treatment: decolorizing ceftiofur acid with decolorizing agent, adjusting pH to acidity after decolorizing, filtering, drying under reduced pressure at 26 deg.C to obtain crude product, and purifying the crude product by recrystallization;
(seventhly) preparing ceftiofur hydrochloride: adding 94mL of acetone, 7mL of water and 10g of ceftiofur acid into a reagent bottle, then adding 4mL of concentrated hydrochloric acid while stirring, supplementing 94mL of acetone after ceftiofur hydrochloride begins to crystallize out, continuing stirring for 34min, filtering, washing with a small amount of acetone, and drying under reduced pressure at 23 ℃ to obtain ceftiofur hydrochloride;
(eighth) preparation of solution one: mixing and stirring 9g of ceftiofur hydrochloride, a dispersing agent, 90ml of tetrahydrofuran and 11ml of water for 0.9h, and filtering to obtain a solution I;
(nine) preparation of solution two: stirring a mixed solution prepared from a salt forming agent, 3.5g of NaOH and 140ml of tetrahydrofuran for 0.9h to prepare a solution II;
(tenth) preparation of ceftiofur sodium: adding the solution into the solution II one drop by one drop, stirring for 44min, filtering, washing with acetone, and drying to obtain ceftiofur sodium salt;
(eleven) grinding: grinding the dried ceftiofur sodium salt into powder;
(twelve) bottling: quantitatively filling ceftiofur sodium powder into a clean reagent bottle according to the specification, and labeling and packaging the sealed reagent bottle;
(thirteen) preservation: the tested ceftiofur sodium vacuum freeze-dried injection is placed in a dry and dark place to be stored for 12 months.
And (3) in the process of preparing the 2-furanmethanethiol through the step (three), adjusting the pH of the solution to be acidic through 5mol/L HCL, so as to be beneficial to improving the adjustment speed of the pH, extracting the solution for 6 times by using 160ml of ethyl alcohol respectively in the process of extracting the solution, and merging ethyl acetate layers.
Step (six) in the process of decoloring, mixing the activated carbon and the adsorption resin 1: 1, removing impurities and oxides in the oil product, and performing recrystallization by using a mass ratio of ethanol to acetone of 2: 1 as a solvent.
And (VIII) in the process of preparing the solution I, polyvinylpyrrolidone is used as a dispersing agent and is also used as a low-temperature preservative, and the polyvinylpyrrolidone does not cause any stimulation to skin, mucous membranes, eyes and the like and has excellent physiological inertia.
In the process of preparing the solution II, the isooctanoic acid is used as a salt forming agent, and the isooctanoic acid has excellent chemical stability.
And (ten) drying the mixed solution by reduced pressure drying at the temperature of 44 ℃ and the pressure of 2.4kPa in the process of preparing the ceftiofur sodium.
As shown in fig. 1 to 4, the milling device for milling the powder in the eleventh step of the invention comprises supporting legs 1, a fixed plate 2, a fixed tube 3, a hopper 4, a power mechanism 6 and a movable milling block 7, wherein the top ends of a plurality of groups of supporting legs 1 are all connected with the bottom end of the fixed plate 2, the fixed tube 3 is installed on the fixed plate 2, the hopper 4 is installed at the input end of the fixed tube 3, the top end of the fixed plate 2 is provided with an inclined block 5, the height of the inclined block 5 is sequentially reduced from right to left, the left end of the fixed tube 3 is communicated with a discharge hole, the fixed tube 3 is fixedly sleeved with the inclined block 5, the power mechanism 6 is installed at the bottom end of the fixed plate 2, the output end of the power mechanism 6 respectively penetrates through the bottom ends of the fixed plate 2 and the inclined block 5 to be connected with the input end of the movable milling block 7, and a static milling block 8 is arranged inside the fixed tube 3; the device also comprises a connecting plate 9, a fixed block 10, first springs 11, sliding plates 12, limiting blocks 13, a push rod 14 and second springs 16, wherein a round hole is arranged at the top end of the connecting plate 9, the output end of the round hole is connected with the input end of a fixed pipe 3, a round groove is arranged in the central area of the bottom end of the fixed block 10, a through hole is communicated with the top side wall in the round groove, the input end of the through hole is connected with the output end of a hopper 4, the through hole is arranged above the round hole, the top end of the connecting plate 9 is contacted with the bottom end of the fixed block 10, mounting grooves are symmetrically arranged at the left end and the right end of the connecting plate 9, fixing grooves are communicated with the inner ends of the two sets of mounting grooves, two sets of first springs 11 are respectively mounted in the fixing grooves, the outer ends of the two sets of first springs 11 are respectively connected with the inner ends of the two sets of sliding plates 12, the two sets of sliding plates 12 are respectively connected with the inner ends of the two sets of limiting blocks 13, arc-shaped grooves are symmetrically arranged on the left side wall and the inner right side wall in the round groove, the outer ends of two groups of limiting blocks 13 are respectively inserted into two groups of arc-shaped grooves, the two groups of arc-shaped grooves are both communicated with operation holes, the two groups of operation holes are both communicated with sliding grooves, two groups of push rods 14 are respectively sleeved with the two groups of operation holes in a sliding manner, limiting plates 15 are respectively arranged on the two groups of push rods 14, the two groups of limiting plates 15 are respectively sleeved with the two groups of sliding grooves in a sliding manner, two groups of second springs 16 are respectively sleeved with the two groups of push rods 14, and two groups of push plates are respectively arranged at the outer ends of the two groups of push rods 14; through setting up connecting plate 9, operating personnel inwards presses simultaneously and moves two sets of push pedals, two sets of push pedals respectively with two sets of push rods 14 cooperation respectively at the spacing downstream inward movement of two sets of handle holes, continue to press down fixed block 10 after butt joint connecting plate 9 and circular slot, two sets of push rods 14 inner respectively with two sets of stopper 13 outer end contact, continue inwards to press and move the push pedal, two sets of stopper 13 keep on extruding and then get into the mounting groove, press down to fixed block 10 bottom and connecting plate 9 top termination after, loosen two sets of push pedals, two sets of first spring 11 respectively with two sets of slides 12 cooperation promote two sets of stoppers 13 respectively and get into two sets of arc walls in, fix connecting plate 9 and fixed block 10, press two sets of push pedals simultaneously during the dismantlement, upwards mention fixed block 10 can, be convenient for change the accessory and maintain the grinding region of device, improve the practicality of device.
The invention relates to a grinding device, which further comprises a horizontal plate 17, third springs 18, movable plates 19 and ejector blocks 20, wherein a fixed hole is formed in the central area of the top end of the horizontal plate 17, a fixed pipe 3 is fixedly sleeved with the fixed hole, two groups of square grooves are symmetrically formed in the top end of the horizontal plate 17, spring grooves are formed in the bottom ends of the two groups of square grooves in a communicated manner, the two groups of third springs 18 are respectively installed in the two groups of spring grooves, the two groups of movable plates 19 are respectively in sliding contact with the two groups of spring grooves, the bottom ends of the two groups of movable plates 19 are respectively connected with the top ends of the two groups of third springs 18, the two groups of ejector blocks 20 are respectively in sliding contact with the two groups of square grooves, the bottom ends of the two groups of ejector blocks 20 are respectively connected with the top ends of the two groups of movable plates 19, and the top ends of the two groups of ejector blocks 20 are respectively in contact with the bottom ends of a fixed block 10; through setting up horizontal plate 17, two sets of third springs 18 cooperate with two sets of fly leaves 19 respectively and jack up fixed block 10 through two sets of kicking blocks 20 under horizontal plate 17's spacing, when dismantling fixed block 10, relieve two sets of stoppers 13 at the spacing back of arc wall through pressing down two sets of push pedals, two sets of kicking blocks 20 jack up fixed block 10, improve the convenience of dismantling fixed block 10 and the practicality of device.
According to the milling device, a sealing gasket 21 is arranged on a connecting plate 9; through setting up sealed the pad 21, sealed pad 21 improves the leakproofness between butt joint back connecting plate 9 and the fixed block 10 with the connecting plate 9 cooperation, improves the practicality of device.
The milling device further comprises a guide pipe 22, the input end of the guide pipe 22 is connected with the output end of the discharge hole, and the output end of the guide pipe 22 penetrates through the left half area of the top end of the fixing plate 2; through setting up pipe 22, pipe 22 and discharge gate cooperation improve the derivation efficiency of deriving the raw materials after smashing, improve the practicality of device.
The milling device further comprises a cover plate 23, a hinge 24 and a handle 25, wherein the lower half area of the right end of the cover plate 23 is hinged with the upper half area of the right end of the hopper 4 through the hinge 24, and the handle 25 is installed on the cover plate 23; through setting up apron 23, apron 23 seals hopper 4 input with the cooperation of hinge 24, and in the dust got into hopper 4 when reducing to smash, the operating personnel of being convenient for opened apron 23 through handle 25 and the cooperation of apron 23, the practicality of improvement device.
According to the milling device, the hopper 4 is provided with the transparent plate 26; through setting up transparent plate 26, transparent plate 26 and hopper 4 cooperation are convenient for operating personnel to observe the inside raw materials of hopper 4, improve the practicality of device.
According to the milling device, the handle 25 is provided with the handle sleeve 27; by providing the handle grip 27, when the operator operates the handle 25, the friction force when the operator holds the handle grip is increased by the handle grip 27, so that the operator can operate the handle grip conveniently, and the practicability of the device is improved.
The milling device further comprises ground feet 28, and a plurality of groups of ground feet 28 are respectively arranged at the bottom ends of a plurality of groups of supporting legs 1; through setting up lower margin 28, the area of contact between lower margin 28 and the landing leg 1 cooperation improvement device and the ground makes the device more stable, improves the practicality of device.
When the milling device works, firstly two groups of limit blocks 13 are relieved from limiting in an arc-shaped groove by pressing two groups of push plates, then two groups of third springs 18 are respectively matched with two groups of movable plates 19 under the limiting of a horizontal plate 17, a fixed block 10 is jacked up through two groups of jacking blocks 20, then the grinding part in the device is maintained, finally an external transmission device of a force mechanism 6 is started, a power mechanism 6 drives a movable grinding block 7 to rotate, then raw materials to be ground are led into a hopper 4, the raw materials are led in through a fixed pipe 3 and are ground uniformly and crushed through the movable grinding block 7 and a static grinding block 8, and the uniformly ground raw materials are guided through an inclined block 5 and then are discharged through a discharge port.
Comparative example:
a preparation process of ceftiofur sodium for vacuum freeze-drying injection comprises the following steps of:
instrument and reagent preparation: preparing an element analyzer, an infrared spectrometer, a nuclear magnetic resonance spectrometer and a mass spectrometer, and preparing a commercially available AR-grade reagent;
(II) reagent detection: detecting and analyzing the prepared reagent by an element analyzer, an infrared spectrometer, a nuclear magnetic resonance spectrometer and a mass spectrometer, and recording related data;
(III) preparing 2-furanmethylthiohydroxy acid: adding 800ml of ethanol, 40ml of water and 45g of NaHS into a reagent bottle, dropwise adding 40g of 2-furoyl chloride at the temperature of 28 ℃ while stirring, reacting for 1.5h, evaporating the ethanol, adding 2500ml of water, adjusting the pH value of the solution to acidity, and performing drying treatment after extraction;
(IV) preparing an intermediate: to the reagent bottle, 800ml of water and 40g of Na were added2CO3Then adding 45g of 7-ACA and 2-furanmethanethiol, stirring uniformly, adjusting the pH of the solution to be neutral, and adding N2Under the protection of (3), heating to 60 ℃ for reaction for 2.5h, cooling to 28 ℃, filtering and washing, and then drying under reduced pressure at 40 ℃ to obtain an intermediate;
(V) preparing ceftiofur acid: adding 15g of intermediate, 30g of AE active ester, 30g of triethylamine and 150ml of dichloromethane into a reagent bottle, reacting for 4 hours at 52 ℃, cooling to 28 ℃, extracting with 100ml of water for three times respectively, and combining water layers;
(VI) decoloring treatment: decolorizing ceftiofur acid with decolorizing agent, adjusting pH to acidity after decolorizing, filtering, drying under reduced pressure at 30 deg.C to obtain crude product, and purifying the crude product by recrystallization;
(seventhly) preparing ceftiofur hydrochloride: adding 100mL of acetone, 8mL of water and 12g of ceftiofur acid into a reagent bottle, then adding 5mL of concentrated hydrochloric acid while stirring, supplementing 100mL of acetone after ceftiofur hydrochloride begins to crystallize out, continuing stirring for 40min, filtering, washing a small amount of acetone, and drying under reduced pressure at 24 ℃ to obtain ceftiofur hydrochloride;
(eighth) preparation of solution one: mixing 10g of ceftiofur hydrochloride, a dispersing agent, 100ml of tetrahydrofuran and 12ml of water, stirring for 1 hour, and filtering to obtain a solution I;
(nine) preparation of solution two: stirring a mixed solution prepared from a salt forming agent, 4g of NaOH and 150ml of tetrahydrofuran for 1 hour to prepare a solution II;
(tenth) preparation of ceftiofur sodium: adding the solution into the solution II one drop by one drop, stirring for 50min, filtering, washing with acetone, and drying to obtain ceftiofur sodium salt;
(eleven) grinding: grinding the dried ceftiofur sodium salt into powder;
(twelve) bottling: quantitatively filling ceftiofur sodium powder into a clean reagent bottle according to the specification, and labeling and packaging the sealed reagent bottle;
(thirteen) preservation: the tested ceftiofur sodium vacuum freeze-dried injection is placed in a dry and dark place to be stored for 4 months.
And (3) in the process of preparing the 2-furanmethanethiol through the step (three), adjusting the pH of the solution to be acidic through 6mol/L HCL, so as to be beneficial to improving the adjustment speed of the pH, extracting the solution for 7 times by using 200ml of ethyl alcohol respectively in the process of extracting the solution, and merging ethyl acetate layers.
And step (VI), in the process of decoloring, removing impurities and oxides in the oil product by using adsorption resin, and in the process of recrystallizing, using a mass ratio of ethanol to acetone of 2: 1 as a solvent.
And (VIII) in the process of preparing the solution I, polyvinylpyrrolidone is used as a dispersing agent and is also used as a low-temperature preservative, and the polyvinylpyrrolidone does not cause any stimulation to skin, mucous membranes, eyes and the like and has excellent physiological inertia.
In the process of preparing the solution II, the isooctanoic acid is used as a salt forming agent, and the isooctanoic acid has excellent chemical stability.
And (ten) drying the mixed solution by reduced pressure drying at the temperature of 50 ℃ and the pressure of 2.5kPa in the process of preparing the ceftiofur sodium.
TABLE 1 Experimental effect data of ceftiofur sodium for injection
Examples 1 to 3 were all obtained by mixing 1: 1, removing impurities from the activated carbon and the adsorption resin in the process of preparing ceftiofur sodium, and storing the mixture for 4 months, 8 months and 12 months respectively under the same conditions, in the comparative example, removing impurities from the adsorption resin in the process of preparing ceftiofur sodium, storing the mixture for 4 months in the same environment, and detecting the residual quantity of the effective substances and related impurities in the examples 1-3 and the comparative example respectively after the storage is finished, wherein the effective substances are beta-lactam rings stable in the ceftiofur, can act on positive gram bacteria and gram negative bacteria for producing beta-lactamase, act on a transcription peptidase to block the synthesis of the sticky peptide, so that the cell walls of the bacteria are deleted to achieve the bactericidal effect, the related impurities comprise complex mixtures of aldehyde, ketone and acid generated after the oxidation of the ceftiofur acid, and the mixtures can not act on the transcription peptidase, the stability of ceftiofur sodium prepared by the method of the invention is greatly improved compared with that of the product prepared in the comparative example, and the experimental data table shows that ceftiofur sodium has good stability, the related impurities are gradually increased along with the increase of the storage time, but the related impurities still do not exceed the limit range specified by the standard, and the stability of ceftiofur sodium is improved by applying the following formula 1: the activated carbon and the adsorption resin of 1 are combined with a filtering and recrystallization mode, so that the purity of the ceftiofur sodium in the subsequent preparation can be effectively improved, and the stability of the ceftiofur sodium is further improved.
It should also be noted that the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Without further limitation, an element defined by the phrase "comprising an … …" does not exclude the presence of other identical elements in the process, method, article, or apparatus that comprises the element.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that various changes in the embodiments and/or modifications of the invention can be made, and equivalents and modifications of some features of the invention can be made without departing from the spirit and scope of the invention.
Claims (3)
1. A preparation process of ceftiofur sodium for vacuum freeze-drying injection is characterized by comprising the following steps:
instrument and reagent preparation: preparing an element analyzer, an infrared spectrometer, a nuclear magnetic resonance spectrometer and a mass spectrometer, and preparing a commercially available AR-grade reagent;
(II) reagent detection: detecting and analyzing the prepared reagent by an element analyzer, an infrared spectrometer, a nuclear magnetic resonance spectrometer and a mass spectrometer, and recording related data;
(III) preparing 2-furanmethylthiohydroxy acid: adding 500-700 ml of ethanol, 30-40 ml of water and 35-45 g of NaHS into a reagent bottle, dropwise adding 30-40 g of 2-furoyl chloride while stirring at the temperature of 24-28 ℃, reacting for 1-1.5 h, evaporating to remove the ethanol, adding 2000-2500 ml of water, adjusting the pH value of the solution to acidity, and drying after extraction;
(IV) preparing an intermediate: adding 600 ml-800 ml of water and 30 g-40 g of Na into a reagent bottle2CO3Then adding 35g to 45g of 7-ACA and 2-furanmethanethiol, uniformly stirring, adjusting the pH of the solution to be neutral, and adding N2Under the protection of (1), heating to 40-60 ℃ for reaction for 2-2.5 h, cooling to 22-28 ℃ for filtration and water washing, and then drying under reduced pressure at 20-40 ℃ to obtain an intermediate;
(V) preparing ceftiofur acid: adding 12g to 15g of intermediate, 20g to 30g of AE active ester, 20g to 30g of triethylamine and 120ml to 150ml of dichloromethane into a reagent bottle, reacting for 3.5h to 4h at 42 ℃ to 52 ℃, cooling to 24 ℃ to 28 ℃, extracting for three times by using 60ml to 100ml of water respectively, and combining water layers;
(VI) decoloring treatment: decolorizing ceftiofur acid by using a decolorizing agent, adjusting the pH value to acidity after decolorizing, filtering, drying under reduced pressure at the temperature of 20-30 ℃ to obtain a crude product, and purifying the crude product by recrystallization; and (VI) in the decoloring treatment process, mixing the activated carbon and the adsorption resin 1: 1, removing impurities and oxides in the oil product, and performing recrystallization by using a mass ratio of ethanol to acetone of 2: 1 as a solvent;
(seventhly) preparing ceftiofur hydrochloride: adding 80-100 mL of acetone, 4-8 mL of water and 8-12 g of ceftiofur acid into a reagent bottle, then adding 2-5 mL of concentrated hydrochloric acid while stirring, supplementing 80-100 mL of acetone after ceftiofur hydrochloride begins to crystallize, continuing stirring for 20-40 min, filtering, washing with a small amount of acetone, and drying under reduced pressure at 20-24 ℃ to obtain ceftiofur hydrochloride;
(eighth) preparation of solution one: mixing 8 g-10 g of ceftiofur hydrochloride, a dispersing agent, 80 ml-100 ml of tetrahydrofuran and 8 ml-12 ml of water, stirring for 0.5 h-1 h, and filtering to obtain a solution I; in the process of preparing the solution I, polyvinylpyrrolidone is used as a dispersing agent and also used as a low-temperature preservative, and the polyvinylpyrrolidone does not cause any stimulation to skin, mucous membrane, eyes and the like and has excellent physiological inertia;
(nine) preparation of solution two: stirring a mixed solution prepared from a salt forming agent, 2-4 g of NaOH and 100-150 ml of tetrahydrofuran for 0.5-1 h to prepare a solution II;
(tenth) preparation of ceftiofur sodium: dripping the solution into the second solution, stirring for 30-50 min, filtering, washing with acetone, and drying to obtain ceftiofur sodium salt; in the process of preparing ceftiofur sodium in the step (ten), drying the mixed solution by reduced pressure drying at the temperature of 45-50 ℃ and under the pressure of 2.0-2.5 kPa;
(eleven) grinding: grinding the dried ceftiofur sodium salt into powder;
the milling device used for milling in the step (eleven) comprises supporting legs (1), a fixing plate (2) and a fixing pipe (3), the grinding machine comprises a hopper (4), a power mechanism (6) and a movable grinding block (7), wherein the top ends of a plurality of groups of supporting legs (1) are connected with the bottom end of a fixed plate (2), a fixed pipe (3) is installed on the fixed plate (2), the hopper (4) is installed at the input end of the fixed pipe (3), an inclined block (5) is arranged at the top end of the fixed plate (2), the height of the inclined block (5) is sequentially reduced from right to left, the left end of the fixed pipe (3) is communicated with a discharge hole, the fixed pipe (3) and the inclined block (5) are fixedly sleeved, the power mechanism (6) is installed at the bottom end of the fixed plate (2), the output end of the power mechanism (6) penetrates through the bottom ends of the fixed plate (2) and the inclined block (5) and is connected with the input end of the movable grinding block (7), and a static grinding block (8) is arranged inside the fixed pipe (3); the device is characterized by further comprising a connecting plate (9), a fixing block (10), first springs (11), sliding plates (12), a limiting block (13), a push rod (14) and second springs (16), wherein a round hole is formed in the top end of the connecting plate (9), the output end of the round hole is connected with the input end of a fixing pipe (3), a round groove is formed in the central area of the bottom end of the fixing block (10), a through hole is formed in the inner top side wall of the round groove in a communicating mode, the input end of the through hole is connected with the output end of a hopper (4), the through hole is formed above the round hole, the top end of the connecting plate (9) is in contact with the bottom end of the fixing block (10), mounting grooves are symmetrically formed in the left end and the right end of the connecting plate (9), fixing grooves are formed in the inner ends of the two groups of mounting grooves in a communicating mode, the two groups of first springs (11) are respectively mounted in the fixing grooves, the outer ends of the two groups of first springs (11) are respectively connected with the inner ends of the two groups of sliding plates (12), and the two groups of sliding plates (12) are respectively in sliding contact with the two groups of fixing grooves, the inner ends of two groups of limiting blocks (13) are respectively connected with the outer ends of two groups of sliding plates (12), arc-shaped grooves are symmetrically formed in the left side wall and the right side wall in the circular groove, the outer ends of the two groups of limiting blocks (13) are respectively inserted into the two groups of arc-shaped grooves, the two groups of arc-shaped grooves are respectively communicated with operation holes, the two groups of operation holes are respectively communicated with sliding grooves, two groups of push rods (14) are respectively sleeved with the two groups of operation holes in a sliding mode, limiting plates (15) are respectively arranged on the two groups of push rods (14), the two groups of limiting plates (15) are respectively sleeved with the two groups of sliding grooves in a sliding mode, the two groups of second springs (16) are respectively sleeved with the two groups of push rods (14), and the two groups of push plates are respectively installed at the outer ends of the two groups of push rods (14);
the device is characterized by further comprising a horizontal plate (17), third springs (18), movable plates (19) and ejector blocks (20), wherein a fixed hole is formed in the central area of the top end of the horizontal plate (17), the fixed pipe (3) is fixedly sleeved with the fixed hole, two groups of square grooves are symmetrically formed in the top end of the horizontal plate (17), spring grooves are formed in the bottom ends of the two groups of square grooves in a communicated manner, the two groups of third springs (18) are respectively installed in the two groups of spring grooves, the two groups of movable plates (19) are respectively in sliding contact with the two groups of spring grooves, the bottom ends of the two groups of movable plates (19) are respectively connected with the top ends of the two groups of third springs (18), the two groups of ejector blocks (20) are respectively in sliding contact with the two groups of square grooves, the bottom ends of the two groups of ejector blocks (20) are respectively connected with the top ends of the two groups of movable plates (19), and the top ends of the two groups of ejector blocks (20) are both in contact with the bottom end of the fixed block (10);
the device also comprises a guide pipe (22), the input end of the guide pipe (22) is connected with the output end of the discharge hole, and the output end of the guide pipe (22) penetrates through the left half area of the top end of the fixing plate (2); the guide pipe (22) is arranged, and the guide pipe (22) is matched with the discharge hole to improve the guiding efficiency of guiding the crushed raw materials and improve the practicability of the device;
the hopper is characterized by further comprising a cover plate (23), a hinge (24) and a handle (25), wherein the lower half area of the right end of the cover plate (23) is hinged with the upper half area of the right end of the hopper (4) through the hinge (24), and the handle (25) is installed on the cover plate (23);
(twelve) bottling: quantitatively filling ceftiofur sodium powder into a clean reagent bottle according to the specification, and labeling and packaging the sealed reagent bottle;
(thirteen) preservation: and (4) storing the tested ceftiofur sodium vacuum freeze-dried injection in a dry and dark place.
2. The preparation process of ceftiofur sodium for vacuum freeze-drying injection according to claim 1, wherein the preparation process comprises the following steps: in the process of preparing the 2-furanmethanethiol in the step (III), the pH value of the solution is adjusted to acidity by 3-6 mol/L HCL, which is beneficial to improving the adjustment speed of the pH value, in the process of extracting the solution, 100-200 ml ethyl alcohol is respectively used for extracting for 5-7 times, and an ethyl acetate layer is combined.
3. The preparation process of ceftiofur sodium for vacuum freeze-drying injection according to claim 1, wherein the preparation process comprises the following steps: in the process of preparing the solution II, the isooctanoic acid is used as a salt forming agent, and the isooctanoic acid has excellent chemical stability.
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