CN116143662A - Continuous production method of cabapilin calcium - Google Patents
Continuous production method of cabapilin calcium Download PDFInfo
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- CN116143662A CN116143662A CN202310437238.XA CN202310437238A CN116143662A CN 116143662 A CN116143662 A CN 116143662A CN 202310437238 A CN202310437238 A CN 202310437238A CN 116143662 A CN116143662 A CN 116143662A
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- C07—ORGANIC CHEMISTRY
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- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/02—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of urea, its salts, complexes or addition compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/02—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of urea, its salts, complexes or addition compounds
- C07C273/14—Separation; Purification; Stabilisation; Use of additives
- C07C273/16—Separation; Purification
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
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Abstract
The invention belongs to the technical field of veterinary drug preparation, and particularly relates to a continuous production method of cabapilin calcium. The continuous production method of the carbapilin calcium provided by the invention comprises the following steps: preparing an aspirin suspension; preparing a calcium nitrate suspension; adding ethanol and ammonia water into an ethanol ammonia feed tank to obtain ethanol ammonia solution; feeding aspirin suspension, calcium nitrate suspension and an glycollic ammonia solution according to the mass ratio through an inlet of a tubular reactor, mixing materials through a spiral pushing rod of the tubular reactor, carrying out continuous synthetic reaction to obtain a cabapilin calcium suspension, cooling, centrifuging, drying to obtain a cabapilin calcium crude product, continuously washing the crude product, centrifuging, and drying by adopting a fluidized bed dryer to obtain cabapilin calcium. The continuous production method of the cabapilin calcium provided by the invention reduces the input amount of raw materials, has high production efficiency, and the prepared cabapilin calcium has high purity, high yield and low content of byproduct salicylic acid.
Description
Technical Field
The invention belongs to the technical field of veterinary drug preparation, and particularly relates to a continuous production method of cabapilin calcium.
Background
The cabapiline calcium is a complex formed by the reaction of aspirin calcium and urea, and the product has high bioavailability, small side effect and good water solubility, and the curative effect is similar to that of aspirin, so the cabapiline calcium is widely valued, and is the only antipyretic analgesic drug approved by relevant departments in China for livestock and poultry oral administration at present. After the oral administration of the carbapirine calcium, the carbapirine calcium is rapidly absorbed by animals and is degraded into salicylic acid in vivo, and the synthesis of prostaglandin by cyclooxygenase and arachidonic acid is inhibited, so that the antipyretic analgesic and anti-inflammatory effects are exerted. The calcium carbapiride has been approved for use in food animals (excluding aquatic animals) such as pigs, chickens, cattle, rabbits, and the like.
Unlike food and other chemical industry, the production process of pharmaceutical industry is generally intermittent production, and the traditional production of cabapilin calcium is carried out by adopting an intermittent titration method, and the method has the problems of low production efficiency, poor product quality, long reaction time and the like. Recent studies have shown that continuous production has greater advantages than batch production in terms of yield, reduced production time, controllability, reproducibility of results, economic benefits, and floor space of equipment.
At present, the method for synthesizing the carbaryl calcium is more, for example, the preparation method disclosed by CN109134315A mainly comprises the steps of adding aspirin and urea into ethanol, stirring for reaction, then adding calcium salt, heating for continuous stirring for reaction, standing and crystallizing the obtained reaction liquid, and performing post-treatment to obtain the carbaryl calcium, or the preparation method disclosed by CN114773232A mainly comprises the steps of dissolving aspirin in methanol or ethanol, dropwise adding ammonia water, adjusting pH, adding calcium nitrate tetrahydrate, then adding urea into the solution, and reacting to obtain the carbaryl calcium, or the preparation method disclosed by CN102382013A mainly comprises the steps of adding aspirin and urea into water for dissolution, adding calcium carbonate into the solution, adding methanol into filtrate after the reaction is finished, and filtering to obtain the carbaryl calcium. The problems of high separation and recovery difficulty and difficult control of the reaction end point are solved by avoiding the problem of explosion hazard caused by the raw materials by not using an ether solvent 2-methoxyethanol, a mixed solvent of ethanol and propanol or ammonia in the raw materials.
For example, the preparation method disclosed in CN114315574a mainly comprises the steps of sequentially mixing aspirin, calcium chloride, a mixed solvent and urea, then adding triethylamine, obtaining the product of cabapine calcium after reaction treatment, adopting DCS to control the addition of a reaction kettle and triethylamine, solving the problem of abnormal reaction, and solving the problem of three wastes caused by the fact that ammonia gas, liquid ammonia or ammonia water is not used in raw materials. For example, the preparation method disclosed in CN102924335A mainly comprises dispersing aspirin, calcium nitrate and urea in ethanol, adding ammonia water under stirring, and solving the problem that the reaction end point is not easy to control due to the adoption of ammonia gas. The preparation method disclosed in CN115572227A mainly comprises the steps of reacting aspirin, calcium oxide or/and calcium hydroxide and urea in methanol, ethanol and/or isopropanol to obtain the cabapine calcium. Adding aspirin and urea into alcohol in CN107344919A, heating to dissolve, dissolving calcium source as liquid A in purified water, dissolving calcium source as liquid B in Wen Dijia liquid B in liquid A, reacting for 5 hr, cooling for crystallization, precipitating a large amount of crystals, centrifuging, and oven drying to obtain carbapilin.
The preparation of the existing aspirin calcium mainly improves the product yield and the product purity of the aspirin calcium, and the synthesis of the cabapine calcium enters into actual production, so that the preparation is mainly aimed at improving the environmental, safety and product quality problems caused by production. However, the existing aspirin calcium has a common point, namely intermittent production in a mode of mixing or dripping by adopting a reaction kettle, and the intermittent production has the problems of low yield, low income, uneven neutralization process, unstable salicylic acid and urea content, difficult recycling of solvents, difficult post-treatment, high yield of byproduct salicylic acid and the like in practical application. However, actual production is more focused on improvement of yield and benefit, so continuous production is a direct way to improve quality and efficiency. For example, the preparation methods of the two cabapine calcium disclosed by CN112321459A and CN112979503A are both intermittent production processes for dropwise adding ethanol ammonia, and the production efficiency is low.
Disclosure of Invention
The invention aims to solve the technical problems caused by intermittent production in the prior art, and provides a continuous production method of the carbapilin calcium, which has the advantages of reduced raw material input, high production efficiency, high purity, high yield and low content of byproduct salicylic acid.
The continuous production method of the carbapilin calcium provided by the invention comprises the following steps:
(1) Adding aspirin and ethanol into an aspirin suspension preparation tank to obtain an aspirin suspension;
(2) Adding urea, calcium nitrate and ethanol into a calcium nitrate suspension material mixing tank to obtain a calcium nitrate suspension;
(3) Adding ethanol and ammonia water into an ethanol ammonia feed tank to obtain ethanol ammonia solution;
(4) Feeding aspirin suspension, calcium nitrate suspension and an glycollic ammonia solution according to the mass ratio through an inlet of a tubular reactor, mixing materials through a spiral propelling rod of the tubular reactor, and carrying out continuous synthetic reaction to obtain a cabapilin calcium suspension; cooling by introducing a cooling medium into a jacket of the tubular reactor in the reaction process;
(5) And (3) centrifuging and drying the cabaretin calcium suspension to obtain a cabaretin calcium crude product, washing the crude product with ethanol, centrifuging, and drying with a fluidized bed dryer to obtain cabaretin calcium.
The water content of the aspirin suspension in the step (1) and the calcium nitrate suspension in the step (2) is 3-10 wt.%.
In the step (1), the mass ratio of aspirin to ethanol is 1 (1.2-1.8).
In the step (2), the mass ratio of the urea to the calcium nitrate to the ethanol is 1 (1.5-3) to 4-6.
The mass ratio of water, ethanol and ammonia in the ethanolamines solution of the step (3) is 5 (0.5-1.5) to 0.5-1.5.
In the step (4), the mass ratio of the aspirin suspension to the calcium nitrate suspension to the glycollic ammonia solution is 1 (1.2-1.5) to 0.2-0.6.
And (4) mixing materials by a spiral pushing rod of the tubular reactor, wherein the residence time in the tubular reactor is 30-60 s.
And (3) cooling to 5-25 ℃ in the step (4).
The pH value of the carbapirine calcium suspension obtained in the step (4) is 3.5-8.5. And adjusting the flow of the raw materials to ensure the pH value of the crude product of the carbapilin calcium.
The ethanol in the step (1), the step (2), the step (3) and the step (5) is an ethanol solution with the weight of 95 percent. The aspirin suspension material preparing tank of the step (1), the calcium nitrate suspension material preparing tank of the step (2), the ethanol ammonia feeding tank of the step (3) and the tubular reactor of the step (4) are all provided with 1 or more.
Specifically, the continuous production method of the carbapilin calcium comprises the following steps:
(1) Adding aspirin and 95wt.% ethanol into an aspirin suspension preparation tank according to a mass ratio of 1 (1.2-1.8) to obtain an aspirin suspension with a water content of 3-10 wt.%.
(2) Adding urea, calcium nitrate and 95wt.% ethanol into a calcium nitrate suspension material tank according to the mass ratio of (1.5-3) (4-6) to obtain the calcium nitrate suspension with the water content of 3-10 wt.%.
(3) Adding ethanol and ammonia water into an ethanol ammonia feed tank to obtain ethanol ammonia solution; the mass ratio of water to ethanol to ammonia is 5 (0.5-1.5) to 0.5-1.5.
The ingredients in the steps (1) to (3) are adopted for 1 time every 5 hours.
(4) The aspirin suspension, the calcium nitrate suspension and the glycollic ammonia solution are mixed and pushed forward by a spiral pushing rod of a tubular reactor according to the mass ratio of 1 (1.2-1.5) (0.2-0.6), and flow out through an inlet above the rear end of the tubular reactor, sequentially enter a second tubular reactor and a third tubular reactor, and undergo continuous synthetic reaction in the residence time of 30-60 s in the tubular reactor to obtain the cabapilin calcium suspension with the pH value of 3.5-8.5; in the reaction process, cooling water is introduced into the jacket of the tubular reactor to 5-25 ℃.
(5) And (3) delivering the cabapilin calcium suspension to a centrifugal drying process, centrifuging by a centrifugal machine to remove ethanol, continuously using 95wt.% ethanol solution to wash the cabapilin calcium crude product in an ethanol washing tank Zhong Xidi, measuring the salicylic acid content of the cabapilin calcium crude product to obtain cabapilin calcium qualified by salicylic acid, delivering the cabapilin calcium qualified by salicylic acid into the centrifugal machine again to centrifugally remove ethanol, and delivering the cabapilin calcium qualified product into a fluidized bed dryer to be dried to obtain the cabapilin calcium qualified product, wherein the salicylic acid content of the cabapilin calcium qualified product is 0.1-0.25 wt.%.
The continuous production method of the cabapilin calcium adopts a plurality of material mixing tanks or feeding tanks, and when one material mixing tank or feeding tank is used for mixing materials, the other material mixing tank or feeding tank is switched to feed materials for a tubular reactor, so that continuous production is realized. The three raw materials (aspirin suspension, calcium nitrate suspension and ethanolamine solution) enter from an inlet below the front end of the tubular reactor, are fully mixed and pushed forward by a spiral stirring shaft, flow out from an inlet above the rear end of the tubular reactor, and enter into a second tubular reactor. After entering from the inlet at the lower part of the front end of the second tubular reactor, the wastewater flows out through the inlet at the upper part of the rear end of the tubular reactor and enters the third tubular reactor. And after entering from an inlet at the lower part of the front end of the third tubular reactor, the crude product of the carbapilin calcium is obtained after flowing out through an inlet at the upper part of the rear end of the tubular reactor. The total residence time of the three reactors is 30-60 s. The reaction temperature is ensured to be about 5-25 ℃ by adjusting cooling water in a jacket of the tubular reactor. And (3) removing ethanol from the crude product of the carbapirin calcium, and delivering the crude product of the carbapirin calcium after primary centrifugation into an ethanol washing tank, and further removing salicylic acid through washing. And delivering the washed crude product of the carbapilin calcium into a centrifugal machine again to remove ethanol. And (5) delivering the crude product of the carbapilin calcium after ethanol removal into a fluidized bed dryer to obtain a qualified carbapilin calcium product.
Compared with the prior art, the invention has the following beneficial effects:
(1) The continuous production method of the carbapilin calcium adopts a tubular reactor, continuously produces, greatly saves the reaction time, and is suitable for industrialized scale-up production.
(2) The continuous production method of the cabapilin calcium effectively reduces the occurrence of side reactions, reduces the input amount of raw materials and improves the yield and quality of products.
(3) The purity of the produced cabapilin calcium reaches 99.9%, the yield reaches 91.0%, and the calcium content and the urea content meet the standards of Chinese animal pharmacopoeia.
Detailed Description
The invention will be further illustrated with reference to specific examples. The mass ratio in the invention is calculated by mass, the content is the mass content, and the yield is the mass yield. All the equipment used in the following examples are existing equipment, and all the raw materials and reagents used are normally commercially available products.
Example 1
The continuous production method of the carbapirine calcium comprises the following steps:
(1) An aspirin suspension having a water content of 6wt.% was obtained by adding 95wt.% ethanol to an aspirin suspension formulation tank at a mass ratio of 1:1.3.
(2) Urea, calcium nitrate and 95wt.% ethanol are added into a calcium nitrate suspension preparation tank according to the mass ratio of 1:1.7:4.5, so as to obtain a calcium nitrate suspension with the water content of 8 wt.%.
(3) Adding 95wt.% ethanol and ammonia water into an ethanol ammonia feed tank to obtain an ethanol ammonia solution; the mass ratio of water to ethanol to ammonia is 5:0.8:0.8.
The ingredients in the steps (1) to (3) are adopted for 1 time every 5 hours.
(4) Feeding aspirin suspension, calcium nitrate suspension and an ethanolamines solution from an inlet below the front end of a tubular reactor according to a mass ratio of 1:1.3:0.35, mixing and advancing by a spiral pushing rod of the tubular reactor, flowing out through an inlet above the rear end of the reactor, sequentially entering a second tubular reactor and a third tubular reactor, and carrying out continuous synthesis reaction in the tubular reactor for 50s to obtain a cabapilin calcium suspension with the pH value of 4; in the reaction process, cooling water is introduced into a jacket of the tubular reactor to 15 ℃.
(5) And (3) delivering the cabapilin calcium suspension to a centrifugal drying process, centrifuging by a centrifugal machine to remove ethanol, continuously using 95wt.% ethanol solution to obtain cabapilin calcium qualified by salicylic acid after washing in an ethanol washing tank Zhong Xidi, delivering the cabapilin calcium qualified by salicylic acid to a centrifugal machine again to centrifuge to remove ethanol, and delivering the cabapilin calcium qualified product to a fluidized bed dryer to dry.
Example 2
The continuous production method of the carbapirine calcium comprises the following steps:
(1) An aspirin suspension having a water content of 10wt.% was obtained by adding 95wt.% ethanol to an aspirin suspension formulation tank at a mass ratio of 1:1.7.
(2) Urea, calcium nitrate and 95wt.% ethanol are added into a calcium nitrate suspension preparation tank according to a mass ratio of 1:2:5, so as to obtain a calcium nitrate suspension with a water content of 10wt.%.
(3) Adding 95wt.% ethanol and ammonia water into an ethanol ammonia feed tank to obtain an ethanol ammonia solution; the mass ratio of water to ethanol to ammonia is 5:1.1:1.
The ingredients in the steps (1) to (3) are adopted for 1 time every 5 hours.
(4) Feeding aspirin suspension, calcium nitrate suspension and an ethanolamines solution from an inlet below the front end of a tubular reactor according to a mass ratio of 1:1.3:0.35, mixing and advancing by a spiral pushing rod of the tubular reactor, flowing out through an inlet above the rear end of the reactor, sequentially entering a second tubular reactor and a third tubular reactor, and carrying out continuous synthesis reaction in the tubular reactor for 60 seconds to obtain a cabapilin calcium suspension with the pH value of 6; in the reaction process, cooling water is introduced into a jacket of the tubular reactor to 20 ℃.
(5) And (3) delivering the cabapilin calcium suspension to a centrifugal drying process, centrifuging by a centrifugal machine to remove ethanol, continuously using 95wt.% ethanol solution to obtain cabapilin calcium qualified by salicylic acid after washing in an ethanol washing tank Zhong Xidi, delivering the cabapilin calcium qualified by salicylic acid to a centrifugal machine again to centrifuge to remove ethanol, and delivering the cabapilin calcium qualified product to a fluidized bed dryer to dry.
Example 3
The continuous production method of the carbapirine calcium comprises the following steps:
(1) An aspirin suspension containing 5wt.% of water was obtained by adding 95wt.% of ethanol to an aspirin suspension formulation tank at a mass ratio of 1:1.2.
(2) Urea, calcium nitrate and 95wt.% ethanol are added into a calcium nitrate suspension preparation tank according to a mass ratio of 1:1.5:4, so as to obtain a calcium nitrate suspension with water content of 5wt.%.
(3) Adding 95wt.% ethanol and ammonia water into an ethanol ammonia feed tank to obtain an ethanol ammonia solution; the mass ratio of water to ethanol to ammonia is 5:0.5:0.5.
The ingredients in the steps (1) to (3) are adopted for 1 time every 5 hours.
(4) Feeding aspirin suspension, calcium nitrate suspension and an ethanolamin solution from an inlet below the front end of a tubular reactor according to a mass ratio of 1:1.2:0.2, mixing and advancing by a spiral pushing rod of the tubular reactor, flowing out through an inlet above the rear end of the reactor, sequentially entering a second tubular reactor and a third tubular reactor, and carrying out continuous synthesis reaction in the tubular reactor for 30 seconds to obtain a cabapilin calcium suspension with the pH value of 7; in the reaction process, cooling water is introduced into a jacket of the tubular reactor to 25 ℃.
(5) And (3) delivering the cabapilin calcium suspension to a centrifugal drying process, centrifuging by a centrifugal machine to remove ethanol, continuously using 95wt.% ethanol solution to obtain cabapilin calcium qualified by salicylic acid after washing in an ethanol washing tank Zhong Xidi, delivering the cabapilin calcium qualified by salicylic acid to a centrifugal machine again to centrifuge to remove ethanol, and delivering the cabapilin calcium qualified product to a fluidized bed dryer to dry.
Example 4
The continuous production method of the carbapirine calcium comprises the following steps:
(1) An aspirin suspension having a water content of 3wt.% was obtained by adding 95wt.% ethanol to an aspirin suspension formulation tank at a mass ratio of 1:1.8.
(2) Urea, calcium nitrate and 95wt.% ethanol are added into a calcium nitrate suspension preparation tank according to a mass ratio of 1:3:6, so as to obtain a calcium nitrate suspension with a water content of 3 wt.%.
(3) Adding 95wt.% ethanol and ammonia water into an ethanol ammonia feed tank to obtain an ethanol ammonia solution; the mass ratio of water to ethanol to ammonia is 5:1.5:1.5.
The ingredients in the steps (1) to (3) are adopted for 1 time every 5 hours.
(4) Feeding aspirin suspension, calcium nitrate suspension and an ethanolamines solution from an inlet below the front end of a tubular reactor according to a mass ratio of 1:1.5:0.6, mixing and advancing by a spiral pushing rod of the tubular reactor, flowing out through an inlet above the rear end of the reactor, sequentially entering a second tubular reactor and a third tubular reactor, and carrying out continuous synthetic reaction in the tubular reactor for 30 seconds to obtain a cabapilin calcium suspension with the pH value of 8.5; in the reaction process, cooling water is introduced into a jacket of the tubular reactor to 5 ℃.
(5) And (3) delivering the cabapilin calcium suspension to a centrifugal drying process, centrifuging by a centrifugal machine to remove ethanol, continuously using 95wt.% ethanol solution to obtain cabapilin calcium qualified by salicylic acid after washing in an ethanol washing tank Zhong Xidi, delivering the cabapilin calcium qualified by salicylic acid to a centrifugal machine again to centrifuge to remove ethanol, and delivering the cabapilin calcium qualified product to a fluidized bed dryer to dry.
Example 5
The continuous production method of the carbapirine calcium comprises the following steps:
(1) An aspirin suspension having a water content of 7wt.% was obtained by adding 95wt.% ethanol to an aspirin suspension formulation tank at a mass ratio of 1:1.6.
(2) Urea, calcium nitrate and 95wt.% ethanol are added into a calcium nitrate suspension preparation tank according to the mass ratio of 1:2.5:5, so as to obtain a calcium nitrate suspension with the water content of 7 wt.%.
(3) Adding 95wt.% ethanol and ammonia water into an ethanol ammonia feed tank to obtain an ethanol ammonia solution; the mass ratio of water to ethanol to ammonia is 5:0.8:1.0.
The ingredients in the steps (1) to (3) are adopted for 1 time every 5 hours.
(4) Feeding aspirin suspension, calcium nitrate suspension and an ethanolamin solution from an inlet below the front end of a tubular reactor according to a mass ratio of 1:1.2:0.5, mixing and advancing by a spiral pushing rod of the tubular reactor, flowing out through an inlet above the rear end of the reactor, sequentially entering a second tubular reactor and a third tubular reactor, and carrying out continuous synthetic reaction in the tubular reactor for 40 seconds to obtain a cabapilin calcium suspension with a pH value of 5; in the reaction process, cooling water is introduced into a jacket of the tubular reactor to 10 ℃.
(5) And (3) delivering the cabapilin calcium suspension to a centrifugal drying process, centrifuging by a centrifugal machine to remove ethanol, continuously using 95wt.% ethanol solution to obtain cabapilin calcium qualified by salicylic acid after washing in an ethanol washing tank Zhong Xidi, delivering the cabapilin calcium qualified by salicylic acid to a centrifugal machine again to centrifuge to remove ethanol, and delivering the cabapilin calcium qualified product to a fluidized bed dryer to dry.
Comparative example 1
An existing batch process for producing cabapine calcium comprising the steps of:
adding aspirin, calcium nitrate tetrahydrate, urea and 95wt.% ethanol into a reaction kettle according to the mass ratio of 1:0.7:0.3:4.5, stirring and mixing, then dropwise adding ammonia water (the mass ratio of 1.3), stirring and reacting for 2 hours after the dropwise adding is finished, continuously adding ethanol, cooling to 15 ℃, preserving heat and crystallizing for 8 hours, sending into a centrifuge for centrifuging to remove ethanol, and then sending into a biconical dryer for drying to obtain a cabapilin calcium qualified product.
Comparative example 2
An existing batch process for producing cabapine calcium comprising the steps of:
adding aspirin, urea, anhydrous calcium nitrate and 95wt.% ethanol into a reaction kettle according to the mass ratio of 1:0.2:0.5:5, stirring and mixing, then introducing ammonia (the mass ratio is 0.1), stirring and reacting for 2 hours after the ammonia is introduced, cooling to 10 ℃, preserving heat and crystallizing for 14 hours, delivering the mixture into a centrifuge for centrifugation to remove the ethanol, and then delivering the mixture into a biconical dryer for drying to obtain a cabapilin calcium qualified product.
Comparative example 3
An existing batch process for producing cabapine calcium comprising the steps of:
adding aspirin, urea, calcium nitrate tetrahydrate and acetone into a reaction kettle according to the mass ratio of 1:0.3:0.6:2.5, stirring and mixing, then introducing ammonia (the mass ratio is 0.12), stirring and reacting for 1h after the ammonia is introduced, cooling to 10 ℃, preserving heat and crystallizing for 4h, delivering into a centrifuge for centrifugation to remove the acetone, and then delivering into a biconical dryer for drying to obtain a cabapilin calcium qualified product.
Comparative example 4
An existing batch process for producing cabapine calcium comprising the steps of:
adding aspirin, urea, calcium nitrate tetrahydrate and 95wt.% ethanol into a reaction kettle according to the mass ratio of 1:0.25:0.55:3, stirring and mixing, adding triethylamine (the mass ratio of 0.25), stirring and reacting for 1h, cooling to 10 ℃, preserving heat and crystallizing for 2h, delivering into a centrifuge for centrifugation to remove ethanol, and delivering into a biconical dryer for drying to obtain a cabapilin calcium qualified product.
Comparative example 5
A method for producing cabapilin calcium, comprising the following steps:
(1) Urea, calcium nitrate and 95wt.% ethanol are added into a material mixing tank according to the mass ratio of 1:1.7:4.5, and then aspirin and 95wt.% ethanol are added according to the mass ratio of 1:1.3, so as to obtain a mixed solution.
(2) Adding 95wt.% ethanol and ammonia water into an ethanol ammonia feed tank to obtain an ethanol ammonia solution; the mass ratio of water to ethanol to ammonia is 5:0.8:0.8.
The ingredients in the steps (1) to (2) are adopted for 1 time every 5 hours.
(3) Feeding the mixed solution and the ethanolamines solution according to the mass ratio of 2.3:0.35 from an inlet below the front end of the tubular reactor, mixing and advancing by a spiral pushing rod of the tubular reactor, flowing out from an inlet above the rear end of the tubular reactor, sequentially entering a second tubular reactor and a third tubular reactor, and carrying out continuous synthesis reaction at the residence time of 50s in the tubular reactor to obtain a kappa-pirin calcium suspension with the pH value of 4; in the reaction process, cooling water is introduced into a jacket of the tubular reactor to 15 ℃.
(4) And (3) delivering the cabapilin calcium suspension to a centrifugal drying process, centrifuging by a centrifugal machine to remove ethanol, continuously using 95wt.% ethanol solution to obtain cabapilin calcium qualified by salicylic acid after washing in an ethanol washing tank Zhong Xidi, delivering the cabapilin calcium qualified by salicylic acid to a centrifugal machine again to centrifuge to remove ethanol, and delivering the cabapilin calcium qualified product to a fluidized bed dryer to dry.
Comparative example 6
A method for producing cabapilin calcium, comprising the following steps:
(1) An aspirin suspension having a water content of 6wt.% was obtained by adding 95wt.% ethanol to an aspirin suspension formulation tank at a mass ratio of 1:1.3.
(2) Urea, calcium nitrate and 95wt.% ethanol are added into a calcium nitrate suspension preparation tank according to the mass ratio of 1:1.7:4.5, so as to obtain a calcium nitrate suspension with the water content of 8 wt.%.
(3) Adding 95wt.% ethanol and ammonia water into an ethanol ammonia feed tank to obtain an ethanol ammonia solution; the mass ratio of water to ethanol to ammonia is 5:0.8:0.8.
The ingredients in the steps (1) to (3) are adopted for 1 time every 5 hours.
(4) Feeding aspirin suspension, calcium nitrate suspension and an ethanolamin solution from an inlet below the front end of a tubular reactor according to a mass ratio of 1:1.8:0.5, mixing and advancing by a spiral pushing rod of the tubular reactor, flowing out through an inlet above the rear end of the reactor, sequentially entering a second tubular reactor and a third tubular reactor, and carrying out continuous synthesis reaction in the tubular reactor for 50s to obtain a cabapilin calcium suspension with the pH value of 4; in the reaction process, cooling water is introduced into a jacket of the tubular reactor to 15 ℃.
(5) And (3) delivering the cabapilin calcium suspension to a centrifugal drying process, centrifuging by a centrifugal machine to remove ethanol, continuously using 95wt.% ethanol solution to obtain cabapilin calcium qualified by salicylic acid after washing in an ethanol washing tank Zhong Xidi, delivering the cabapilin calcium qualified by salicylic acid to a centrifugal machine again to centrifuge to remove ethanol, and delivering the cabapilin calcium qualified product to a fluidized bed dryer to dry.
The cabaretin calcium products prepared in the examples and the comparative examples are analyzed, the salicylic acid content and the content of related substances in the products are detected by adopting an HPLC method, the calcium content and the calcium content of the cabaretin in the products are detected by adopting a titration method, the content of urea is detected by adopting a spectrophotometry method, the requirement of the Chinese veterinary pharmacopoeia on salicylic acid is less than or equal to 1.0 percent, the requirement of other single impurities in related substances is less than or equal to 0.05 percent, the calcium content of the cabaretin is more than or equal to 98 percent, the requirement of the calcium content of the cabaretin is 8.0-8.9 percent, the requirement of the urea content of the cabaretin calcium is 12.9-13.3 percent, and the detection results are shown in table 1.
TABLE 1 detection results
As can be seen from the table, the carbapirine calcium product prepared by adopting the continuous production method has higher purity and higher content, and the urea content, the calcium content and the salicylic acid content all meet the requirements of Chinese animal pharmacopoeia. The conventional batch method (titration) according to comparative example 1 was superior to example 1 in terms of purity, but the yield of the product was not ideal, and the batch production method according to comparative example 1 was used to produce a continuous production method of the present invention with an actual annual yield of 1800 to 2000t, an actual annual yield of 3600 to 4000t, and an actual yield and a yield were both high. The comparative example 2 adopts anhydrous calcium nitrate with high process cost and low productivity, the actual annual output is 400-500 t, the anhydrous calcium nitrate is difficult to purchase and has unstable quality, and the requirements of Chinese animal pharmacopoeia are not met. The acetone process adopted in comparative example 3 has higher yield, but the product quality is very unstable, and salicylic acid, related substances and urea do not meet the requirements of Chinese animal pharmacopoeia. Comparative example 4 has sticky yield, is not easy to dry, has ammonia smell and has poor solubility by adopting a triethylamine process. In the comparative example 5, two raw materials are reacted by adopting a tubular reactor, and the prepared product has lower yield and purity and does not meet the requirements of Chinese animal pharmacopoeia. The three raw materials in the comparative example 6 are fed according to the proportion of 1:1.8:0.5, and are difficult to meet the requirements of Chinese animal pharmacopoeia.
Of course, the foregoing is merely preferred embodiments of the present invention and is not to be construed as limiting the scope of the embodiments of the present invention. The present invention is not limited to the above examples, and those skilled in the art will appreciate that the present invention is capable of equally varying and improving within the spirit and scope of the present invention.
Claims (10)
1. A continuous production method of cabapilin calcium is characterized in that: the method comprises the following steps:
(1) Adding aspirin and ethanol into an aspirin suspension preparation tank to obtain an aspirin suspension;
(2) Adding urea, calcium nitrate and ethanol into a calcium nitrate suspension material mixing tank to obtain a calcium nitrate suspension;
(3) Adding ethanol and ammonia water into an ethanol ammonia feed tank to obtain ethanol ammonia solution;
(4) Feeding aspirin suspension, calcium nitrate suspension and an glycollic ammonia solution according to the mass ratio through an inlet of a tubular reactor, mixing materials through a spiral propelling rod of the tubular reactor, and carrying out continuous synthetic reaction to obtain a cabapilin calcium suspension; cooling by introducing a cooling medium into a jacket of the tubular reactor in the reaction process;
(5) And (3) centrifuging and drying the cabaretin calcium suspension to obtain a cabaretin calcium crude product, washing the crude product with ethanol, centrifuging, and drying with a fluidized bed dryer to obtain cabaretin calcium.
2. The continuous production method of the carbapirine calcium according to claim 1, wherein: the water content of the aspirin suspension in the step (1) and the calcium nitrate suspension in the step (2) is 3-10 wt.%.
3. The continuous production method of the carbapirine calcium according to claim 1, wherein: in the step (1), the mass ratio of aspirin to ethanol is 1 (1.2-1.8).
4. The continuous production method of the carbapirine calcium according to claim 1, wherein: in the step (2), the mass ratio of the urea to the calcium nitrate to the ethanol is 1 (1.5-3) to 4-6.
5. The continuous production method of the carbapirine calcium according to claim 1, wherein: the mass ratio of water, ethanol and ammonia in the ethanolamines solution of the step (3) is 5 (0.5-1.5) to 0.5-1.5.
6. The continuous production method of the carbapirine calcium according to claim 1, wherein: in the step (4), the mass ratio of the aspirin suspension to the calcium nitrate suspension to the glycollic ammonia solution is 1 (1.2-1.5) to 0.2-0.6.
7. The continuous production method of the carbapirine calcium according to claim 1, wherein: and (4) mixing materials by a spiral pushing rod of the tubular reactor, wherein the residence time in the tubular reactor is 30-60 s.
8. The continuous production method of the carbapirine calcium according to claim 1, wherein: and (3) cooling to 5-25 ℃ in the step (4).
9. The continuous production method of the carbapirine calcium according to claim 1, wherein: the pH value of the carbapirine calcium suspension obtained in the step (4) is 3.5-8.5.
10. The continuous production method of the carbapirine calcium according to claim 1, wherein: the ethanol in the step (1), the step (2), the step (3) and the step (5) is an ethanol solution with the weight of 95 percent.
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