CN112979503A - Preparation method of carbasalate calcium - Google Patents
Preparation method of carbasalate calcium Download PDFInfo
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- CN112979503A CN112979503A CN202110210099.8A CN202110210099A CN112979503A CN 112979503 A CN112979503 A CN 112979503A CN 202110210099 A CN202110210099 A CN 202110210099A CN 112979503 A CN112979503 A CN 112979503A
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- calcium
- aspirin
- carbasalate
- reaction
- carbapenem
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- 229960004105 carbasalate calcium Drugs 0.000 title claims abstract description 47
- VYMUGTALCSPLDM-UHFFFAOYSA-L carbasalate calcium Chemical compound [Ca+2].NC(N)=O.CC(=O)OC1=CC=CC=C1C([O-])=O.CC(=O)OC1=CC=CC=C1C([O-])=O VYMUGTALCSPLDM-UHFFFAOYSA-L 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 60
- 229960001138 acetylsalicylic acid Drugs 0.000 claims abstract description 57
- ZCCIPPOKBCJFDN-UHFFFAOYSA-N calcium nitrate Chemical compound [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 claims abstract description 39
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims abstract description 35
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims abstract description 24
- 229910052791 calcium Inorganic materials 0.000 claims abstract description 24
- 239000011575 calcium Substances 0.000 claims abstract description 24
- 239000002904 solvent Substances 0.000 claims abstract description 19
- 239000004202 carbamide Substances 0.000 claims abstract description 17
- 238000001816 cooling Methods 0.000 claims abstract description 17
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000001914 filtration Methods 0.000 claims abstract description 13
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 11
- 239000013078 crystal Substances 0.000 claims abstract description 9
- 239000007787 solid Substances 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 7
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 6
- 238000000967 suction filtration Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 8
- 239000012535 impurity Substances 0.000 abstract description 2
- KRALOLGXHLZTCW-UHFFFAOYSA-L calcium;2-acetyloxybenzoate Chemical compound [Ca+2].CC(=O)OC1=CC=CC=C1C([O-])=O.CC(=O)OC1=CC=CC=C1C([O-])=O KRALOLGXHLZTCW-UHFFFAOYSA-L 0.000 description 26
- 239000000047 product Substances 0.000 description 23
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 239000000273 veterinary drug Substances 0.000 description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- KZTZJUQNSSLNAG-UHFFFAOYSA-N aminoethyl nitrate Chemical compound NCCO[N+]([O-])=O KZTZJUQNSSLNAG-UHFFFAOYSA-N 0.000 description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 5
- 229960004889 salicylic acid Drugs 0.000 description 5
- ZHJGWYRLJUCMRT-UHFFFAOYSA-N 5-[6-[(4-methylpiperazin-1-yl)methyl]benzimidazol-1-yl]-3-[1-[2-(trifluoromethyl)phenyl]ethoxy]thiophene-2-carboxamide Chemical compound C=1C=CC=C(C(F)(F)F)C=1C(C)OC(=C(S1)C(N)=O)C=C1N(C1=C2)C=NC1=CC=C2CN1CCN(C)CC1 ZHJGWYRLJUCMRT-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- PAWQVTBBRAZDMG-UHFFFAOYSA-N 2-(3-bromo-2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=C1F PAWQVTBBRAZDMG-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000003907 antipyretic analgesic agent Substances 0.000 description 2
- ICSSIKVYVJQJND-UHFFFAOYSA-N calcium nitrate tetrahydrate Chemical compound O.O.O.O.[Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ICSSIKVYVJQJND-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 244000144977 poultry Species 0.000 description 2
- 235000013594 poultry meat Nutrition 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- BTZJQYVYGCCNHY-UHFFFAOYSA-N calcium;urea Chemical compound [Ca].NC(N)=O BTZJQYVYGCCNHY-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of carbasalate calcium, which comprises the following steps: (1) dissolving aspirin and calcium nitrate in an alcohol solvent to form a solution A, then dropwise adding ethanolamine into the solution A at 0-4 ℃ for reaction, controlling the temperature of a reaction system to be 4-7 ℃ and the pH to be 7-8.5 during the reaction, separating out aspirin calcium white solid, and filtering after the reaction is finished to obtain an aspirin calcium wet product; (2) dissolving a wet aspirin calcium product and urea in an alcohol solvent, and reacting at 30-35 ℃ for 2-2.5 hours to obtain a calcium aspirin-urea complex reaction solution; (3) and (3) cooling the complex reaction liquid obtained in the step (2), growing crystals, filtering and drying to obtain the carbasalate calcium. The invention adopts anhydrous calcium nitrate and ethanolamine to prepare the carbasalate calcium, ensures that a reaction system is introduced without water, and has high yield of the synthesized carbasalate calcium, less impurities and high content which can reach more than 99.3 percent.
Description
Technical Field
The invention relates to the field of veterinary drug preparation, and in particular relates to a preparation method of carbasalate calcium.
Background
The carbasalate calcium is a complex of aspirin calcium and urea, has the same metabolic characteristics and pharmacological action as aspirin, and has the effects of relieving fever, easing pain, resisting inflammation and inhibiting platelet aggregation. Carbasalate calcium is the only internationally approved antipyretic analgesic for all food animals such as pigs, chickens, cattle, rabbits, etc., and has been loaded in the european pharmacopoeia. The carbasalate calcium is three new veterinary drugs in China, and is the only antipyretic analgesic approved by the Ministry of agriculture for poultry. The veterinary drug has good water solubility, and can be used for drinking water and mixing with materials; the veterinary drug has no residue in animal body after administration, so there is no need for withdrawal period. The carbasalate calcium is applied to livestock and poultry breeding, and has good market prospect.
At present, the preparation method of the carbasalate calcium mainly comprises the following steps:
adding aspirin, calcium nitrate tetrahydrate and urea into methanol or ethanol, heating and stirring until the aspirin, the calcium nitrate tetrahydrate and the urea are completely dissolved, cooling to 0-5 ℃, introducing ammonia gas for reaction, heating to 40-45 ℃ after reaction liquid is neutral, and reacting to obtain a finished product of the carbasalate calcium. The process has the problems that: the pH of the reaction liquid is adjusted by ammonia gas, the reaction end point is not easy to control, the ammonia gas is insufficient, the aspirin reaction is incomplete, the ammonia gas is excessive, the carbasalate calcium is easy to hydrolyze, the salicylic acid content is high, the product purity is influenced, the ammonia gas is volatile, the environment pollution is serious, and the product quality controllability is poor.
Adding aspirin, calcium nitrate tetrahydrate and urea into methanol or ethanol, heating and stirring until the aspirin, the calcium nitrate tetrahydrate and the urea are completely dissolved, cooling to 0-5 ℃, slowly adding a certain amount of ammonia water, and heating to react to obtain a finished product of the carbasalate calcium. Although the process solves the problems that the reaction end point is not easy to control in production and the production operation has potential safety hazard, the concentration of ammonia water is generally 25-28%, the rest 72-75% is water, and the water in calcium nitrate tetrahydrate is added, so that the content of methanol or ethanol in the reaction system is reduced, and the yield is reduced to a certain extent compared with an anhydrous ethanol solvent because the calcium carbiprine is very easy to dissolve in water.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a preparation method of carbapenem calcium, which adopts anhydrous calcium nitrate to replace tetrahydrate calcium nitrate and adopts ethanolamine to replace ammonia water, ensures that no water is introduced into a reaction system, and is not only beneficial to the improvement of the yield of the carbapenem calcium, but also beneficial to the stability of the concentration of an alcohol solvent.
In order to achieve the purpose, the invention adopts the following technical scheme:
a preparation method of carbasalate calcium comprises the following steps:
(1) dissolving aspirin and calcium nitrate in an alcohol solvent to form a solution A, then dropwise adding ethanolamine into the solution A at 0-4 ℃ for reaction, controlling the temperature of a reaction system to be 4-7 ℃ and the pH to be 7-8.5 during the reaction, separating out aspirin calcium white solid, and filtering after the reaction is finished to obtain an aspirin calcium wet product;
(2) dissolving aspirin calcium wet product and urea in an alcohol solvent, and reacting for 2-2.5 h (e.g. 2.1h, 2.2h, 2.3h and 2.4h) at 30-35 ℃ (e.g. 31 ℃, 32 ℃, 33 ℃ and 34 ℃) to obtain aspirin calcium-urea complex reaction liquid;
(3) and (3) cooling the complex reaction liquid obtained in the step (2), growing crystals, filtering and drying to obtain the carbasalate calcium.
In the above preparation method, as a preferred embodiment, the step (1) specifically includes: adding aspirin and calcium nitrate into an alcohol solvent, stirring at 25-30 ℃ (e.g., 26 ℃, 27 ℃, 28 ℃ and 29 ℃) to completely dissolve the aspirin and calcium nitrate to form a solution A, then cooling the solution A to 0-4 ℃ (e.g., 0.5 ℃, 1 ℃, 2 ℃, 3 ℃ and 3.5 ℃), slowly dropwise adding (dropwise adding at the speed of 0.5-2mL/30 s) ethanolamine into the solution A for reaction, controlling the temperature of a reaction system to be 4-7 ℃ (e.g., 4.5 ℃, 5.0 ℃, 5.5 ℃, 6.0 ℃ and 6.5 ℃) during the reaction, and controlling the pH to be 7-8.5 (e.g., 7.2, 7.5, 8.0, 8.2 and 8.4) to precipitate aspirin calcium white solid, and filtering to remove clear liquid to obtain an aspirin calcium wet product.
In the invention, at the beginning of the reaction, due to the existence of carboxyl, the reaction system is acidic, and the pH value is 1-2. With the addition of ethanolamine, the pH is gradually increased, after the ethanolamine is added, the pH of a reaction system is controlled to be about 7-8.5, and the aspirin is guaranteed to be completely salified; the aspirin calcium is easy to hydrolyze due to overhigh pH value; the pH was too low and aspirin did not react. Therefore, the invention can judge the reaction end point through pH.
In the above preparation method, as a preferred embodiment, the step (3) specifically includes: cooling the complex reaction solution obtained in the step (2) to 0-4 ℃ (e.g., 0.5 ℃, 1 ℃, 2 ℃, 3 ℃, 3.5 ℃), growing crystals for 2-3 h (e.g., 2.2h, 2.5h, 2.8h), then filtering and removing clear liquid to obtain a wet carbapenem calcium product, and drying the wet carbapenem calcium product for 4-5 h (e.g., 4.2h, 4.5h, 4.8h) in vacuum at 45-60 ℃ (e.g., 47 ℃, 50 ℃, 55 ℃, 58 ℃) to obtain the carbapenem calcium.
In the above production method, as a preferred embodiment, the alcohol in the step (1) is ethanol.
In the above production method, as a preferred embodiment, the calcium nitrate in the step (1) is anhydrous calcium nitrate.
In the above production method, as a preferred embodiment, the ethanolamine in the step (1) is monoethanolamine.
In the above preparation method, as a preferred embodiment, the mass-to-volume ratio of aspirin to ethanol in step (1) is 1 (2-4) (e.g., 1:2.2, 1:2.5, 1:3.0, 1:3.5, 1:3.8), and the unit is g/ml.
In the above preparation method, as a preferred embodiment, the mass ratio of aspirin to anhydrous calcium nitrate in the step (1) is 1 (0.46 to 0.64) (e.g., 1:0.48, 1:0.50, 1:0.55, 1:0.60, 1: 0.62).
In the above production method, as a preferred embodiment, the mass ratio of aspirin to monoethanolamine in step (1) is 1 (0.34 to 0.37) (e.g., 1:0.35, 1: 0.36).
In the above preparation method, as a preferred embodiment, the alcohol in the step (2) is ethanol.
In the above preparation method, as a preferred embodiment, the mass-to-volume ratio of the calcium aspirin and the ethanol in the step (2) is 1 (2-3) (e.g., 1:2.2, 1:2.4, 1:2.5, 1:2.7, 1:2.9) in g/ml.
In the above preparation method, as a preferred embodiment, the mass ratio of the calcium aspirin and the urea in the step (2) is 1 (0.2-0.25) (e.g., 1:0.21, 1:0.22, 1:0.23, 1: 0.24).
In the above preparation method, as a preferred embodiment, the yield of the carbasalate calcium product is 95% or more and the content thereof is 99.3% or more; more preferably, the yield of the carbasalate calcium product is 95.2% -97.6%, and the content is 99.3% -99.8%.
The invention adopts a two-step method to synthesize the carbasalate calcium, the first step is as follows: aspirin reacts with anhydrous calcium nitrate and ethanolamine to obtain aspirin calcium and ethanolamine nitrate, aspirin calcium wet product is obtained through filtering, and ethanolamine nitrate is filtered out along with the filtrate. The second step is that: the aspirin calcium and the urea are complexed in the alcohol solution to generate the carbasalate calcium.
Because the carbapenem calcium is very soluble in water, the adoption of anhydrous calcium nitrate and ethanolamine ensures that the system is carried out in an anhydrous state, avoids the dissolution of the carbapenem calcium and improves the yield. In addition, the concentration of the alcohol solvent is not affected by the dilution effect of water, so that the stability of the concentration of the alcohol solvent can be ensured.
By adopting the technical scheme of the invention, the formed ethanolamine nitrate has quite high solubility in ethanol, so that the generated ethanolamine nitrate by-product is dissolved in the ethanol and cannot be separated out. In the reaction process of preparing aspirin calcium by using calcium nitrate and ammonia water in the prior art, the solubility of the formed by-product ammonium nitrate in ethanol is lower than that of ethanolamine nitrate, so that the ammonium nitrate is easy to remain in an aspirin calcium wet product and is difficult to clean and remove, and the purity of the aspirin calcium is influenced.
Meanwhile, because the carbapenem calcium is prepared by adopting the two-step method, the byproduct ethanolamine nitrate generated in the first step is filtered out along with the filtrate, and cannot be brought into the complex reaction in the second step, so that the content of the carbapenem calcium in the final product is ensured, and the stability of the product quality is ensured.
In the invention, the technical characteristics can be freely combined to form a new technical scheme under the condition of not conflicting with each other.
The chemical reaction equation of the preparation method is as follows:
compared with the prior art, the invention has the following beneficial effects:
1. according to the preparation method of the carbapenem calcium, anhydrous calcium nitrate is adopted to replace tetrahydrate calcium nitrate, ethanolamine is adopted to replace ammonia water, the anhydrous introduction of a reaction system is ensured, and the improvement of the yield of the carbapenem calcium and the stability of the concentration of an alcohol solvent are facilitated.
2. The invention adopts a two-step method to prepare the carbasalate calcium, and the synthesized carbasalate calcium has less impurities, high content and stable product quality, and the content can stably reach more than 99.3 percent.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are only for the purpose of the present invention and are not intended to limit the scope of the present invention. It should be understood that various changes and modifications can be made by those skilled in the art after reading the disclosure of the present invention, and equivalents fall within the scope of the appended claims.
Example 1
A preparation method of carbasalate calcium comprises the following steps:
(1) adding 100g of aspirin and 46g of calcium nitrate into 300ml of ethanol solvent, completely dissolving at 25-30 ℃, cooling to 0-4 ℃, slowly dropwise adding 36g of ethanolamine, controlling the temperature to be 4-7 ℃, adjusting the pH to be 8, separating out white aspirin calcium solid, and filtering to obtain an aspirin calcium wet product.
(2) Dissolving 20g of aspirin calcium wet product and urea in 300ml of ethanol solvent, and reacting for 2 hours at the temperature of 30 ℃.
(3) And (3) cooling the reaction liquid to 0-4 ℃, growing the crystals for 2 hours, and performing suction filtration to obtain the wet carbasalate calcium product. The wet product of the carbapenem calcium is dried for 4 hours under vacuum at 45 ℃ to prepare 120g of the carbapenem calcium with the yield of 95.2 percent. According to the test of '2019 version carbasalate calcium veterinary drug standard bulletin board', the content of the carbasalate calcium is 99.8%, and the content of the salicylic acid is about 0.2%.
Example 2
A preparation method of carbasalate calcium comprises the following steps:
(1) adding 100g of aspirin and 55g of calcium nitrate into 250ml of ethanol solvent, completely dissolving at 25-30 ℃, cooling to 0-4 ℃, slowly dropwise adding 35g of ethanolamine, controlling the temperature to be 4-7 ℃, adjusting the pH to be 7.5, separating out white aspirin calcium solid, and filtering to obtain the wet aspirin calcium product.
(2) Dissolving aspirin calcium wet product and urea 22g in 250ml ethanol solvent, and reacting at 33 ℃ for 2 h.
(3) And (3) cooling the reaction liquid to 0-4 ℃, growing crystals for 2h, performing suction filtration, and drying at 45 ℃ for 4h in vacuum to obtain 123g of carbasalate calcium with the yield of 97.6%. According to the test of '2019 version carbasalate calcium veterinary drug standard bulletin board', the content of the carbasalate calcium is 99.5%, and the content of the salicylic acid is 0.4%.
Example 3
A preparation method of carbasalate calcium comprises the following steps:
(1) adding 100g of aspirin and 60g of calcium nitrate into 280ml of ethanol solvent, completely dissolving at 30 ℃, then cooling to 0-4 ℃, slowly dropwise adding 35g of ethanolamine, controlling the temperature to be 4-7 ℃, adjusting the pH to be 7.5, separating out white aspirin calcium solid, and filtering to obtain the wet aspirin calcium product.
(2) Dissolving aspirin calcium wet product and urea 22g in 250ml ethanol solvent, and reacting at 33 ℃ for 2 h.
(3) And (3) cooling the reaction liquid to 0-4 ℃, growing the crystals for 2h, performing suction filtration, and drying at 45 ℃ for 4h in vacuum to obtain 122g of carbasalate calcium with the yield of 96.8%. The content of the carbasalate calcium is 99.7 percent and the content of the salicylic acid is 0.2 percent according to the test of the standard bulletin board of carbasalate calcium veterinary drug of 2019.
Comparative example
A preparation method of carbasalate calcium comprises the following steps:
(1) sequentially adding 100g of aspirin, 46g of calcium nitrate and 20g of urea into 500mL of ethanol, and stirring and dissolving for 30min at room temperature; then cooling, adding 38mL of ammonia water at a speed of 1-2 mL per minute under the conditions of 2-4 ℃ and stirring, then heating to 25-28 ℃, and reacting for 2 hours to obtain a reaction solution;
(2) and (2) cooling the reaction liquid prepared in the step (1) to 0-4 ℃, growing crystals for 2 hours, then carrying out suction filtration, and carrying out vacuum drying at the temperature of 45 ℃ for 4 hours to obtain 100.8g of carbasalate calcium, wherein the yield is 90%. The content of the carbasalate calcium is 98.5 percent and the content of the salicylic acid is 0.66 percent according to the test of the standard bulletin board of carbasalate calcium veterinary drug of 2019.
Claims (10)
1. A preparation method of carbasalate calcium, which is characterized by comprising the following steps:
(1) dissolving aspirin and calcium nitrate in an alcohol solvent to form a solution A, then dropwise adding ethanolamine into the solution A at 0-4 ℃ for reaction, controlling the temperature of a reaction system to be 4-7 ℃ and the pH to be 7-8.5 during the reaction, separating out aspirin calcium white solid, and filtering after the reaction is finished to obtain an aspirin calcium wet product;
(2) dissolving a wet aspirin calcium product and urea in an alcohol solvent, and reacting at 30-35 ℃ for 2-2.5 hours to obtain a calcium aspirin-urea complex reaction solution;
(3) and (3) cooling the complex reaction liquid obtained in the step (2), growing crystals, filtering and drying to obtain the carbasalate calcium.
2. The method of preparing carbasalate calcium according to claim 1, wherein:
the step (1) specifically comprises: adding aspirin and calcium nitrate into an alcohol solvent, stirring at 25-30 ℃ to completely dissolve the aspirin and the calcium nitrate to form a solution A, then cooling the solution A to 0-4 ℃, slowly dropwise adding ethanolamine into the solution A to react, controlling the temperature of a reaction system to be 4-7 ℃ and the pH to be 7-8.5 during the reaction, separating out aspirin calcium white solid, and filtering to remove clear liquid to obtain an aspirin calcium wet product.
3. The method of preparing carbapenem calcium of claim 2, wherein:
the step (3) specifically comprises: and (3) cooling the complex reaction liquid obtained in the step (2) to 0-4 ℃, growing the crystals for 2-3 h, then carrying out suction filtration to remove clear liquid to obtain a wet product of the carbapenem calcium, and drying the wet product of the carbapenem calcium in vacuum at the temperature of 45-60 ℃ for 4-5 h to obtain the carbapenem calcium.
4. The method of preparing carbasalate calcium according to claim 1, wherein: the alcohol in the step (1) is ethanol;
preferably, the calcium nitrate in step (1) is anhydrous calcium nitrate;
preferably, the ethanolamine in the step (1) is monoethanolamine.
5. The method of preparing carbapenem calcium of claim 4, wherein: the mass-volume ratio of aspirin to ethanol in the step (1) is 1 (2-4), and the unit is g/ml.
6. The method of preparing carbapenem calcium of claim 4, wherein: the mass ratio of the aspirin to the anhydrous calcium nitrate in the step (1) is 1 (0.46-0.64).
7. The method of preparing carbapenem calcium of claim 4, wherein: the mass ratio of the aspirin to the monoethanolamine in the step (1) is 1 (0.34-0.37).
8. The method of preparing carbasalate calcium according to claim 1, wherein: the alcohol in the step (2) is ethanol;
preferably, the mass-to-volume ratio of the aspirin calcium to the ethanol in the step (2) is 1 (2-3), and the unit is g/ml.
9. The method of preparing carbasalate calcium according to claim 1, wherein: the mass ratio of the aspirin calcium to the urea in the step (2) is 1 (0.2-0.25).
10. The process for the preparation of carbapenem calcium of any of claims 1 to 9, wherein: the yield of the carbasalate calcium product is more than 95% and the content is more than 99.3%;
preferably, the yield of the carbasalate calcium product is 95.2% -97.6%, and the content is 99.3% -99.8%.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114315574A (en) * | 2021-12-31 | 2022-04-12 | 河南豫辰药业股份有限公司 | Preparation method of carbasalate calcium |
| CN116143662A (en) * | 2023-04-23 | 2023-05-23 | 新华制药（高密）有限公司 | Continuous production method of cabapilin calcium |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109111378A (en) * | 2018-10-29 | 2019-01-01 | 河南后羿实业集团有限公司 | A kind of preparation method of carbasalate calcium |
| CN112321459A (en) * | 2020-11-25 | 2021-02-05 | 济南久隆医药科技有限公司 | Method for synthesizing carbasalate calcium |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109111378A (en) * | 2018-10-29 | 2019-01-01 | 河南后羿实业集团有限公司 | A kind of preparation method of carbasalate calcium |
| CN112321459A (en) * | 2020-11-25 | 2021-02-05 | 济南久隆医药科技有限公司 | Method for synthesizing carbasalate calcium |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114315574A (en) * | 2021-12-31 | 2022-04-12 | 河南豫辰药业股份有限公司 | Preparation method of carbasalate calcium |
| CN116143662A (en) * | 2023-04-23 | 2023-05-23 | 新华制药（高密）有限公司 | Continuous production method of cabapilin calcium |
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