CN113045534A - Ibuprofen ketalization process - Google Patents
Ibuprofen ketalization process Download PDFInfo
- Publication number
- CN113045534A CN113045534A CN202110307825.8A CN202110307825A CN113045534A CN 113045534 A CN113045534 A CN 113045534A CN 202110307825 A CN202110307825 A CN 202110307825A CN 113045534 A CN113045534 A CN 113045534A
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- CN
- China
- Prior art keywords
- ibuprofen
- organic solvent
- water
- reaction
- ketal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 229960001680 ibuprofen Drugs 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title claims abstract description 15
- 238000005907 ketalization reaction Methods 0.000 title claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000003960 organic solvent Substances 0.000 claims abstract description 17
- SLCVBVWXLSEKPL-UHFFFAOYSA-N neopentyl glycol Chemical compound OCC(C)(C)CO SLCVBVWXLSEKPL-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 15
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 claims description 14
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 13
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 claims description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 12
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 239000003208 petroleum Substances 0.000 abstract description 6
- 230000007613 environmental effect Effects 0.000 abstract description 4
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 abstract description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 238000009835 boiling Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000012797 qualification Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 230000001754 anti-pyretic effect Effects 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- -1 Baotan Chemical compound 0.000 description 1
- 206010029240 Neuritis Diseases 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 239000003907 antipyretic analgesic agent Substances 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 210000000777 hematopoietic system Anatomy 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
Abstract
The invention provides an ibuprofen ketalization process, wherein an ibuprofen intermediate chlorone is added into an organic solvent, neopentyl glycol and a catalyst are added, and the mixture is heated and reacts with water to obtain a ketal; the invention aims to select a novel organic solvent to replace petroleum ether to be used in the production process of ibuprofen, wherein the novel organic solvent is a single component with low toxicity and meets the requirements of pharmaceutical standards; meanwhile, the water-carrying requirement of the ibuprofen process can be met, and the reaction rate is appropriate; but also can be recycled to the maximum extent, achieve the purposes of clean production and economic production, and reduce the environmental protection pressure.
Description
The technical field is as follows:
the invention relates to a production process method of ibuprofen as an antipyretic analgesic, belonging to the field of pharmaceutical chemicals.
Technical background:
ibuprofen, chemical name: 2- (4-isobutylphenyl) propionic acid, which is a non-steroidal anti-inflammatory drug, has 16-32 times stronger anti-inflammatory, analgesic and antipyretic effects than aspirin. Compared with common anti-inflammatory analgesic drugs, the compound preparation has strong effect and small side effect, has no obvious side effect on liver, kidney and hematopoietic system, and particularly has small side effect on gastrointestinal tract, and can be taken by patients who cannot tolerate aspirin, Baotan, indomethacin and other drugs. The product can be used for treating rheumatic arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, neuritis, pharyngolaryngitis, and bronchitis. Ibuprofen is the only commonly recommended antipyretic for children by the world health organization and the FDA in the United states, and is a recognized first choice anti-inflammatory for children.
In the original process of ibuprofen, petroleum ether is used as a solvent, ibuprofen intermediate chlorone is added into the petroleum ether (0.8-1.2:1) (W/W), stirring is carried out, after water washing and layering, neopentyl glycol and a catalyst are added, heating and water carrying reaction are carried out, and ketal is obtained; the petroleum ether plays a role in promoting the reaction with water in the reaction process; however, the compound belongs to other solvents except I, II and III in ICH (International Conference on harmony of Techn technical requirement for drug registration), the toxicity is not clear, and certain hidden troubles of product quality exist; meanwhile, the petroleum ether is a multi-component mixture, the components are complex, and the components with high boiling point and low boiling point are both present, so that the problem of recycling is brought, and the production cost is high; meanwhile, the method brings great difficulty to environmental protection tail gas treatment and waste water COD treatment, and does not meet the requirements of green development and economic development.
The invention content is as follows:
the invention provides an ibuprofen ketalization process, which comprises the steps of adding an ibuprofen intermediate chlorone into an organic solvent, adding neopentyl glycol and a catalyst, heating and carrying out water-carrying reaction to obtain a ketal, and is characterized in that the organic solvent is n-hexane, n-heptane, cyclohexane and methylcyclohexane; the mass ratio of the chloroketone to the organic solvent is 1: 1.5; the reaction temperature is 85-115 ℃ and the reaction time is 8 h.
The organic solvent is n-heptane or methylcyclohexane.
The ibuprofen ketalizing process is characterized in that the organic solvent is methylcyclohexane.
The invention aims to select a novel organic solvent to replace petroleum ether to be used in the ibuprofen production process, and the selected novel organic solvent is preferably a single component, has low toxicity and meets the requirements of pharmaceutical standards; meanwhile, the water-carrying requirement of the ibuprofen process can be met, and the reaction rate is appropriate; but also can be recycled to the maximum extent, achieve the purposes of clean production and economic production, and reduce the environmental protection pressure.
A novel organic solvent is selected to be applied in the production process of ibuprofen, and the method is characterized in that: firstly, a single component is immiscible with water and does not generate side reaction with reactants, catalysts, products and the like; secondly, the boiling point of the water is close to that of water, so that the water is easier to take out; the toxicity is low, and the compound is suitable to be used as a solvent for producing bulk drugs; the boiling point of the catalyst is within the reaction temperature range (85-130 ℃), and the reaction rate is proper; economy and environmental protection.
The method comprises the following specific steps: respectively adding ibuprofen intermediate chlorone into different organic solvents (0.8-1.2:1) (W/W), stirring, washing with water for layering, adding neopentyl glycol and a catalyst, and heating to react with water to obtain the ketal.
Detailed Description
Example (b):
example 1 dissolving 50g of ibuprofen chloroketone in 75g of n-hexane, stirring for dissolution, adding 10ml of water for washing, adding 30g of neopentyl glycol and 1ml of dilute sulfuric acid, heating for reflux reaction with water, carrying out reaction at the reaction temperature of 85-85.9 ℃, and sampling for analysis after 8 h.
The analysis result shows that the sample is chloroketone, which indicates that the chloroketone is not converted into ketal under the condition (the qualification indexes are that the content of the ketal is more than or equal to 90 percent and the content of the chloroketone is less than or equal to 2.1 percent).
Example 2 ibuprofen chloroketone 50g is dissolved in cyclohexane 75g, after stirring and dissolution, water 10ml is added for washing, neopentyl glycol 30g and dilute sulphuric acid 1ml are added, temperature is raised for reflux reaction with water, reaction temperature is 85-92.3 ℃, and sampling is carried out after 8 h.
The analysis result shows that the ketal content in the sample is 9.67 percent, the chloroketone content is 88.52 percent, and the reaction result is not ideal (the qualification indexes are that the ketal content is more than or equal to 90 percent and the chloroketone content is less than or equal to 2.1 percent).
Example 3. dissolving 50g of ibuprofen chloroketone in 75g of n-heptane, stirring for dissolution, adding 10ml of water for washing, adding 30g of neopentyl glycol and 1ml of dilute sulfuric acid, heating for reflux reaction with water, carrying out reaction at the reaction temperature of 85-105.4 ℃, and sampling after 8 h.
The analysis result shows that the ketal content in the sample is 87.91%, the chlorone content is 11.65%, and the reaction result does not reach the standard (the qualification index is that the ketal content is more than or equal to 90%, and the chlorone content is less than or equal to 2.1%).
Example 4. dissolving 50g of ibuprofen chloroketone in 75g of methylcyclohexane, stirring and dissolving, then adding 10ml of water for washing, adding 27g of neopentyl glycol and 1ml of dilute sulfuric acid, heating to carry out reflux reaction with water, carrying out reaction at the reaction temperature of 85-113.7 ℃, and sampling after 8 h.
The analysis result shows that the ketal content in the sample is 96.91 percent, the chloroketone content is 1.85 percent, and the reaction result does not reach the standard (the qualification index is that the ketal content is more than or equal to 90 percent and the chloroketone content is less than or equal to 2.1 percent).
Claims (3)
1. An ibuprofen ketalization process, add ibuprofen midbody chlorone into organic solvent, add neopentyl glycol and catalyst, heat up and take water reaction to get ketal, its characteristic is that said organic solvent is n-hexane, n-heptane, cyclohexane, methylcyclohexane; the mass ratio of the chloroketone to the organic solvent is 1: 1.5; the reaction temperature is 85-115 ℃ and the reaction time is 8 h.
2. The process of claim 1, wherein the organic solvent is selected from the group consisting of n-heptane and methylcyclohexane.
3. A process according to claim 1 or 2, wherein the organic solvent is methylcyclohexane.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110307825.8A CN113045534A (en) | 2021-03-23 | 2021-03-23 | Ibuprofen ketalization process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110307825.8A CN113045534A (en) | 2021-03-23 | 2021-03-23 | Ibuprofen ketalization process |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113045534A true CN113045534A (en) | 2021-06-29 |
Family
ID=76514376
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110307825.8A Pending CN113045534A (en) | 2021-03-23 | 2021-03-23 | Ibuprofen ketalization process |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113045534A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4623736A (en) * | 1982-07-09 | 1986-11-18 | The Upjohn Company | Arylalkanoic acid process improvement |
| CN101234963A (en) * | 2008-03-05 | 2008-08-06 | 江苏八巨药业有限公司 | Industrial synthesis technique for DL-naproxen |
| CN103524478A (en) * | 2013-10-24 | 2014-01-22 | 青岛科技大学 | Device and method for shortening ketalation time in ibuprofen synthesis process |
| CN110563694A (en) * | 2019-09-24 | 2019-12-13 | 山东新华制药股份有限公司 | preparation method of ibuprofen intermediate |
-
2021
- 2021-03-23 CN CN202110307825.8A patent/CN113045534A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4623736A (en) * | 1982-07-09 | 1986-11-18 | The Upjohn Company | Arylalkanoic acid process improvement |
| CN101234963A (en) * | 2008-03-05 | 2008-08-06 | 江苏八巨药业有限公司 | Industrial synthesis technique for DL-naproxen |
| CN103524478A (en) * | 2013-10-24 | 2014-01-22 | 青岛科技大学 | Device and method for shortening ketalation time in ibuprofen synthesis process |
| CN110563694A (en) * | 2019-09-24 | 2019-12-13 | 山东新华制药股份有限公司 | preparation method of ibuprofen intermediate |
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| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20210629 |