CN111333506A - Method for synthesizing carbasalate calcium - Google Patents
Method for synthesizing carbasalate calcium Download PDFInfo
- Publication number
- CN111333506A CN111333506A CN202010333013.6A CN202010333013A CN111333506A CN 111333506 A CN111333506 A CN 111333506A CN 202010333013 A CN202010333013 A CN 202010333013A CN 111333506 A CN111333506 A CN 111333506A
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- CN
- China
- Prior art keywords
- calcium
- synthesizing
- aspirin
- solvent
- carbasalate
- Prior art date
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Links
- 238000000034 method Methods 0.000 title claims abstract description 25
- 229960004105 carbasalate calcium Drugs 0.000 title claims abstract description 17
- 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 17
- 230000002194 synthesizing effect Effects 0.000 title claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 30
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims abstract description 19
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229960001138 acetylsalicylic acid Drugs 0.000 claims abstract description 18
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims abstract description 16
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 12
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000004202 carbamide Substances 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 16
- 229910052791 calcium Inorganic materials 0.000 claims description 16
- 239000011575 calcium Substances 0.000 claims description 16
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 11
- UNMYWSMUMWPJLR-UHFFFAOYSA-L Calcium iodide Chemical group [Ca+2].[I-].[I-] UNMYWSMUMWPJLR-UHFFFAOYSA-L 0.000 claims description 5
- 229940046413 calcium iodide Drugs 0.000 claims description 5
- 229910001640 calcium iodide Inorganic materials 0.000 claims description 5
- 229910001622 calcium bromide Inorganic materials 0.000 claims description 4
- WGEFECGEFUFIQW-UHFFFAOYSA-L calcium dibromide Chemical compound [Ca+2].[Br-].[Br-] WGEFECGEFUFIQW-UHFFFAOYSA-L 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 239000012535 impurity Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- PAWQVTBBRAZDMG-UHFFFAOYSA-N 2-(3-bromo-2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=C1F PAWQVTBBRAZDMG-UHFFFAOYSA-N 0.000 abstract description 12
- ZCCIPPOKBCJFDN-UHFFFAOYSA-N calcium nitrate Chemical compound [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 abstract description 7
- 238000001308 synthesis method Methods 0.000 abstract description 6
- 238000001035 drying Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000004880 explosion Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- FKPHRFXRZILVQT-NUBCRITNSA-N C1C=CN2[C@H]1CC2=O.[Ca] Chemical compound C1C=CN2[C@H]1CC2=O.[Ca] FKPHRFXRZILVQT-NUBCRITNSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 210000003298 dental enamel Anatomy 0.000 description 3
- 239000002360 explosive Substances 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 1
- 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 1
- 230000000694 effects Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a novel safe synthesis method of carbasalate calcium, which takes aspirin, anhydrous calcium chloride, urea, liquid ammonia and a catalyst as raw materials and takes methanol or ethanol as a solvent for chemical synthesis; thereby producing no ammonium nitrate, no concentration of ammonium nitrate solvent and no explosion hazard with drying of ammonium nitrate. The yield reaches more than 95 percent, and the purity is more than or equal to 99.8 percent (LC). Compared with the traditional process, the method does not use calcium nitrate, does not generate ammonium nitrate with great potential safety hazard, greatly improves the production safety, has low cost and is easy for industrial production.
Description
Technical Field
The invention relates to the field of chemical synthesis, in particular to a novel safe synthesis method of carbasalate calcium.
Background
Cabapirine calcium is a derivative of aspirin, which was first developed and successfully developed by DSM in the Netherlands. The product has high bioavailability, low side effect and good water solubility, and is widely regarded.
At present, the preparation method of the carbasalate calcium mainly comprises the following steps:
1. the traditional process takes acetone and ethanol as a mixed solvent, aspirin, calcium nitrate tetrahydrate and urea are sequentially added, ammonia gas is introduced at room temperature until the ammonia gas is not absorbed, the finished product of the carbasalate calcium is obtained after stirring, the yield is 89-93%, and the process has two problems: A. acetone and ethanol are mixed solvents and are difficult to recover, and B and a byproduct are ammonium nitrate, and the byproduct is usually easy to explode.
2. In chinese patent document CN101575305A, calcium nitrate is used as a raw material, and ammonium nitrate is present as a by-product.
3. In chinese patent document CN02924335B, calcium nitrate is used as a raw material, and ammonium nitrate is present as a by-product.
Disclosure of Invention
In view of the above, the present invention provides a novel method for safely synthesizing carbasalate calcium, which does not generate explosive ammonium nitrate and can improve the product purity.
A method for synthesizing carbasalate calcium comprises the following synthetic raw materials: the synthesis raw materials are chemically synthesized by taking methanol or ethanol as a solvent, and the reaction is carried out to generate the calcium carbilopirine.
According to the synthesis method of the carbasalate calcium, the mass ratio of aspirin, anhydrous calcium chloride, urea, liquid ammonia and the catalyst is 1: (1-2): (1-1.2): (1-1.5): (0.01-0.1).
According to the synthesis method of the carbapenem calcium, the mass ratio of the solvent to the aspirin is 10: 1.
according to the application of the method for synthesizing the carbasalate calcium, the organic solvent is ethanol.
According to the application, the water content of the solvent is lower than 0.1%, the aspirin content is 99.9%, and the impurity content is 0.1%.
According to the application of the method for synthesizing the carbasalate calcium, the catalyst is calcium iodide or calcium bromide.
According to the application of the method for synthesizing carbasalate calcium, the reaction temperature of the chemical synthesis is 0-60 ℃.
According to the application, ammonia gas is introduced in the chemical synthesis process, and the operation is carried out under normal pressure.
According to the carbasalate calcium synthesis method, the ammonia gas is introduced above the liquid level.
According to the carbapenem calcium synthesis method, the mass of the anhydrous calcium chloride is 1-1.2 times of that of aspirin.
After the technology provided by the invention is adopted, the method for synthesizing the carbapenem calcium according to the embodiment of the invention has the following beneficial effects.
1) Taking aspirin, anhydrous calcium chloride, urea, liquid ammonia and a catalyst as raw materials, and taking methanol or ethanol as a solvent to carry out chemical synthesis to generate carbasalate calcium; the yield reaches more than 95 percent, and the purity is more than or equal to 99.8 percent (LC). After the calcium carbiopilin is generated by using anhydrous calcium chloride through reaction, no explosive ammonium nitrate is generated, and the generated calcium chloride is easily dissolved in a methanol or ethanol solution, so that the purity of the product is improved. The invention has the advantages of good product quality, no ammonium nitrate, no wastewater, high production safety, low cost and easy industrial production.
Detailed Description
Various preferred embodiments of the present invention will be described below. The following description is provided to facilitate understanding of example embodiments of the invention as defined by the claims and their equivalents. It includes various specific details to assist understanding, but they are to be construed as merely illustrative. Accordingly, those skilled in the art will recognize that various changes and modifications can be made to the embodiments described herein without departing from the scope and spirit of the present invention. Also, in order to make the description clearer and simpler, a detailed description of functions and configurations well known in the art will be omitted.
Example 1
A method for synthesizing carbapenem calcium comprises the steps of chemically synthesizing aspirin, anhydrous calcium chloride, urea, liquid ammonia and a catalyst by taking methanol or ethanol as a solvent, and reacting to generate the carbapenem calcium. The mass ratio of the aspirin, the anhydrous calcium chloride, the urea, the liquid ammonia and the catalyst is 1: (1-2): (1-1.2): (1-1.5): (0.01-0.1). The catalyst is calcium iodide or calcium bromide. The mass ratio of the solvent to aspirin is 10: 1. the water content of the solvent is lower than 0.1%, the aspirin content is 99.9%, and the impurity content is 0.1%.
The reaction temperature of the chemical synthesis is 0-60 deg.c.
And introducing ammonia gas in the chemical synthesis process, and operating under normal pressure in a mode of introducing the ammonia gas above the liquid level.
According to the method for synthesizing the carbapenem calcium, aspirin, anhydrous calcium chloride, urea, liquid ammonia and a catalyst are used as raw materials, methanol or ethanol is used as a solvent for chemical synthesis, and the carbapenem calcium is generated through reaction; the yield reaches more than 95 percent, and the purity is more than or equal to 99.8 percent (LC). After the calcium carbiopilin is generated by using anhydrous calcium chloride through reaction, no explosive ammonium nitrate is generated, and the generated calcium chloride is easily dissolved in a methanol or ethanol solution, so that the purity of the product is improved. The invention has the advantages of good product quality, no ammonium nitrate, no wastewater, high production safety, low cost and easy industrial production.
Example 2
3000L of ethanol and 500 kg of aspirin are added into a 5000L enamel reaction kettle. After uniform stirring, firstly adding 339 kg of anhydrous calcium chloride, then adding 167 kg of urea, then adding 5 kg of calcium iodide as a catalyst, reducing the temperature to 0 ℃, introducing 71 kg of liquid ammonia gas, stirring at high speed for 4 hours, reducing the rotating speed to 5 revolutions per minute by using a frequency converter, homogenizing crystals, centrifuging after 12 hours, washing and pulping by using 3 times of anhydrous ethanol, and drying the calcium carbapenem obtained by centrifuging to obtain a product; the yield was 95.2% and the purity was 99.8% (LC).
Example 3
3000L of ethanol and 500 kg of aspirin are added into a 5000L enamel reaction kettle. After uniform stirring, firstly adding 339 kg of anhydrous calcium chloride, then adding 167 kg of urea, then adding 5 kg of calcium bromide as a catalyst, reducing the temperature to 0 ℃, introducing 71 kg of liquid ammonia gas, stirring at high speed for 4 hours, reducing the rotating speed to 5 revolutions per minute by using a frequency converter, homogenizing crystals, centrifuging after 12 hours, washing and pulping by using 3 times of anhydrous ethanol, and drying the calcium carbapenem obtained by centrifuging to obtain a product; yield 90.1% and purity 99.1% (LC).
Example 4
3000L of methanol and 500 kg of aspirin are put into a 5000L enamel reaction kettle. After uniform stirring, firstly adding 339 kg of anhydrous calcium chloride, then adding 167 kg of urea, then adding 5 kg of calcium iodide as a catalyst, reducing the temperature to 0 ℃, introducing 71 kg of liquid ammonia gas, stirring at high speed for 4 hours, reducing the rotating speed to 5 revolutions per minute by using a frequency converter, homogenizing crystals, centrifuging after 12 hours, washing and pulping by using 3 times of anhydrous methanol, and drying the calcium carbapenem obtained by centrifuging to obtain a product; yield 86% and purity 98.8% (LC).
The present invention has been described in detail, and the principle and embodiments of the present invention are explained herein by using specific examples, which are only used to help understand the method and the core idea of the present invention; meanwhile, for a person skilled in the art, according to the idea of the present invention, there may be variations in the specific embodiments and the application scope, and in summary, the content of the present specification should not be construed as a limitation to the present invention.
From the above description of the embodiments, it will be apparent to those skilled in the art that the present invention may be practiced. Of course, the above listed cases are only examples, and the present invention is not limited thereto. It should be understood by those skilled in the art that other modifications or simplifications according to the technical solution of the present invention may be appropriately applied to the present invention and should be included in the scope of the present invention.
Claims (10)
1. The method for synthesizing the carbasalate calcium is characterized by comprising the following synthetic raw materials: the synthesis raw materials are chemically synthesized by taking methanol or ethanol as a solvent, and the reaction is carried out to generate the calcium carbilopirine.
2. The method for synthesizing carbapenem calcium of claim 1, wherein the mass ratio of aspirin, anhydrous calcium chloride, urea, liquid ammonia, and catalyst is 1: (1-2): (1-1.2): (1-1.5): (0.01-0.1).
3. The method for synthesizing carbapenem calcium according to claim 1 or 2, wherein the mass ratio of the solvent to aspirin is 10: 1.
4. the method as claimed in claim 3, wherein the organic solvent is ethanol.
5. The method as claimed in claim 3, wherein the solvent has a water content of less than 0.1%, the aspirin content is 99.9%, and the impurity content is 0.1%.
6. The method of claim 1 or 2, wherein the catalyst is calcium iodide or calcium bromide.
7. The method for synthesizing carbasalate calcium according to claim 1 or 2, wherein the reaction temperature of said chemical synthesis is (0-60) C.
8. The method for synthesizing carbasalate calcium according to claim 1 or 2, wherein ammonia gas is introduced during the chemical synthesis and the operation is performed under normal pressure.
9. The method for synthesizing carbapenem calcium of claim 8, wherein the ammonia gas is introduced above the liquid level.
10. The method for synthesizing carbapenem calcium according to claim 1 or 2, wherein the mass of the anhydrous calcium chloride is 1-1.2 times the mass of aspirin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010333013.6A CN111333506A (en) | 2020-04-24 | 2020-04-24 | Method for synthesizing carbasalate calcium |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010333013.6A CN111333506A (en) | 2020-04-24 | 2020-04-24 | Method for synthesizing carbasalate calcium |
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| CN111333506A true CN111333506A (en) | 2020-06-26 |
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| CN202010333013.6A Pending CN111333506A (en) | 2020-04-24 | 2020-04-24 | Method for synthesizing carbasalate calcium |
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Cited By (1)
| 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 | A kind of preparation method of carbasalate calcium |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101575305A (en) * | 2009-06-01 | 2009-11-11 | 浙江圣效化学品有限公司 | Preparation method of carbasalate calcium |
| CN102382013A (en) * | 2011-08-16 | 2012-03-21 | 青岛康地恩药业股份有限公司 | Preparation method of carbasalate calcium |
| CN110724057A (en) * | 2019-12-05 | 2020-01-24 | 山东省化工研究院 | Preparation method of carbasalate calcium |
| CN110776420A (en) * | 2019-11-18 | 2020-02-11 | 山东省化工研究院 | Synthesis process of carbasalate calcium |
-
2020
- 2020-04-24 CN CN202010333013.6A patent/CN111333506A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101575305A (en) * | 2009-06-01 | 2009-11-11 | 浙江圣效化学品有限公司 | Preparation method of carbasalate calcium |
| CN102382013A (en) * | 2011-08-16 | 2012-03-21 | 青岛康地恩药业股份有限公司 | Preparation method of carbasalate calcium |
| CN110776420A (en) * | 2019-11-18 | 2020-02-11 | 山东省化工研究院 | Synthesis process of carbasalate calcium |
| CN110724057A (en) * | 2019-12-05 | 2020-01-24 | 山东省化工研究院 | Preparation method of 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 | A kind of preparation method of carbasalate calcium |
| CN114315574B (en) * | 2021-12-31 | 2024-11-29 | 河南豫辰药业股份有限公司 | Preparation method of cabapilin calcium |
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