CN118239835A - Method for reducing residual quantity of rearranged ester in ibuprofen preparation process - Google Patents
Method for reducing residual quantity of rearranged ester in ibuprofen preparation process Download PDFInfo
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- CN118239835A CN118239835A CN202410333336.3A CN202410333336A CN118239835A CN 118239835 A CN118239835 A CN 118239835A CN 202410333336 A CN202410333336 A CN 202410333336A CN 118239835 A CN118239835 A CN 118239835A
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- ibuprofen
- sodium salt
- reducing
- rearranged
- crude
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- 150000002148 esters Chemical class 0.000 title claims abstract description 48
- 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 39
- 229960001680 ibuprofen Drugs 0.000 title claims abstract description 37
- 238000000034 method Methods 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- PTTPUWGBPLLBKW-UHFFFAOYSA-M sodium;2-[4-(2-methylpropyl)phenyl]propanoate Chemical compound [Na+].CC(C)CC1=CC=C(C(C)C([O-])=O)C=C1 PTTPUWGBPLLBKW-UHFFFAOYSA-M 0.000 claims abstract description 63
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 32
- 230000008707 rearrangement Effects 0.000 claims abstract description 22
- 238000001914 filtration Methods 0.000 claims abstract description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000013078 crystal Substances 0.000 claims abstract description 17
- 238000003756 stirring Methods 0.000 claims abstract description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000005406 washing Methods 0.000 claims abstract description 9
- 238000002156 mixing Methods 0.000 claims abstract description 8
- 230000020477 pH reduction Effects 0.000 claims abstract description 8
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 7
- 239000000706 filtrate Substances 0.000 claims abstract description 7
- 238000004042 decolorization Methods 0.000 claims abstract description 5
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 10
- 239000012266 salt solution Substances 0.000 claims description 5
- GJSDKKUJJNIQQV-UHFFFAOYSA-N (3-chloro-2,2-dimethylpropyl) 2-[4-(2-methylpropyl)phenyl]propanoate Chemical group CC(C)CC1=CC=C(C(C)C(=O)OCC(C)(C)CCl)C=C1 GJSDKKUJJNIQQV-UHFFFAOYSA-N 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000006555 catalytic reaction Methods 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000001276 controlling effect Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 231100000024 genotoxic Toxicity 0.000 description 3
- 230000001738 genotoxic effect Effects 0.000 description 3
- KXUHSQYYJYAXGZ-UHFFFAOYSA-N isobutylbenzene Chemical compound CC(C)CC1=CC=CC=C1 KXUHSQYYJYAXGZ-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- -1 rearrangement ester Chemical compound 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000003907 antipyretic analgesic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 231100000446 genotoxin Toxicity 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000012452 mother liquor Substances 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
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/47—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of organic chemistry, in particular to a method for reducing the residual quantity of rearranged ester in the preparation process of ibuprofen. The method for reducing the residual quantity of rearranged ester in the ibuprofen preparation process comprises the following steps: (1) Completely dissolving crude ibuprofen sodium salt in 60-80 ℃ water, adding active carbon for decolorization, filtering, reducing the temperature of filtrate to below 40 ℃, adding ethanol, mixing and stirring, adding seed crystal, continuing stirring, reducing the temperature to 0-10 ℃, standing, filtering, and washing to obtain recrystallized ibuprofen sodium salt; (2) Completely dissolving the recrystallized ibuprofen sodium salt in water, adding hydrochloric acid for acidification, crystallizing and filtering to obtain crude ibuprofen. The invention adopts a recrystallization mode to purify the crude ibuprofen sodium salt, thereby removing residual rearrangement esters in the crude ibuprofen sodium salt, and the rearrangement esters in the prepared crude ibuprofen are not detected.
Description
Technical Field
The invention relates to the technical field of organic chemistry, in particular to a method for reducing the residual quantity of rearranged ester in the preparation process of ibuprofen.
Background
Ibuprofen is a antipyretic analgesic, non-steroidal anti-inflammatory drug, and by inhibiting cyclooxygenase, prostaglandin synthesis is reduced, and analgesic and anti-inflammatory effects are produced; has antipyretic effect by regulating the central nervous system by hypothalamic body temperature.
At present, the common industrial synthesis process of ibuprofen is a molecular rearrangement method disclosed in patent CN1082022A, and ibuprofen is synthesized by taking isobutylbenzene as a starting material and carrying out molecular rearrangement, hydrolysis and acidification under the catalysis of chloroketone and ketal. Wherein, an intermediate alpha-methyl-4- (2-methylpropyl) phenylacetic acid-3-chloro-2, 2-dimethylpropyl ester, namely rearrangement ester, is obtained after molecular rearrangement under catalysis, and the structural formula is as follows:
The rearrangement ester is taken as a chloro compound, is suspected genotoxic impurity, and needs to strictly control the residual quantity of the rearrangement ester in the product ibuprofen. In CN1082022a, after molecular rearrangement under catalysis, a sodium hydroxide solution is added into a reaction solution containing rearranged ester, after reflux hydrolysis, a crude ibuprofen salt is obtained by crystallization, unreacted rearranged ester is removed by petroleum ether extraction, and then the ibuprofen is obtained by acidification and refining, wherein the reaction formula is as follows:
the residual content of the rearranged ester in the crude ibuprofen salt obtained by the method is higher than 120ppm, and the rearranged ester is difficult to thoroughly remove in the subsequent acidification and refining procedures, so that the residual content of the rearranged ester is higher.
Patent CN110590546a discloses a method for controlling rearrangement of esters in ibuprofen preparation process, adding water and sodium hydroxide into sodium ibuprofen salt after petroleum ether extraction to make reflux reaction, further hydrolyzing residual rearrangement esters, then decolorizing with active carbon, filtering, washing with water, acidifying with hydrochloric acid, filtering and preparing crude ibuprofen product. The residual rearrangement ester in the obtained ibuprofen crude product is not detected, and the harsh requirement of drug evaluation on the limit of suspected genotoxic substances is met, but the method needs secondary hydrolysis reaction, and has the advantages of higher energy consumption and longer time consumption.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims at: the method for reducing the residual quantity of the rearranged ester in the ibuprofen preparation process is provided, and a recrystallization mode is adopted to purify the crude ibuprofen sodium salt, so that the residual rearranged ester in the crude ibuprofen sodium salt is removed, the rearranged ester in the prepared crude ibuprofen is not detected, and the severe requirement of drug evaluation on the limit of suspected genotoxins is met.
The method for reducing the residual quantity of rearranged ester in the ibuprofen preparation process comprises the following steps:
(1) Completely dissolving crude ibuprofen sodium salt in 60-80 ℃ water, adding active carbon for decolorization, filtering, reducing the temperature of filtrate to below 40 ℃, adding ethanol, mixing and stirring, adding seed crystal, continuing stirring, reducing the temperature to 0-10 ℃, standing, filtering, and washing to obtain recrystallized ibuprofen sodium salt;
(2) Completely dissolving the recrystallized ibuprofen sodium salt in water, adding hydrochloric acid for acidification, crystallizing and filtering to obtain crude ibuprofen.
In the invention, the rearrangement ester is alpha-methyl-4- (2-methylpropyl) phenylacetic acid-3-chloro-2, 2-dimethylpropyl ester, and the structural formula is as follows:
In the invention, the crude ibuprofen sodium salt is obtained by taking isobutylbenzene as a starting raw material and sequentially carrying out molecular rearrangement, hydrolysis and crystallization under the catalysis of chloroketone, ketal, and the content of rearranged ester is higher than 120ppm; such as the crude ibuprofen sodium salt obtained in patent CN1082022 a.
In the step (1), the water consumption is 10-12 times of the mass of the crude ibuprofen sodium salt.
In the step (1), the dosage of the activated carbon is 5-10% of the mass of the crude ibuprofen sodium salt; when the active carbon is decolorized, the temperature of the crude ibuprofen sodium salt solution is controlled to be 60-80 ℃.
In the step (1), the dosage of the ethanol is 15-20 times of the mass of the crude ibuprofen sodium salt; adding ethanol, mixing and stirring for 5-15min.
In the step (1), the seed crystal is ibuprofen sodium salt pure product (purity is more than or equal to 99.9%), and the dosage of the seed crystal is 1-2% of the mass of the crude ibuprofen sodium salt.
In the step (1), after adding seed crystal, stirring is continued for 5-15min.
In the step (1), standing until crystals are completely separated out, filtering, and washing with ethanol to obtain recrystallized ibuprofen sodium salt. The filtrate and the washing solution were mixed, ethanol and most of the water were distilled off, and then secondary recrystallization was performed as a mother liquor.
In the step (2), the water is used in an amount which is 8 to 10 times the mass of the recrystallized ibuprofen sodium salt.
In the step (2), hydrochloric acid is added until the pH value of the system is lower than 2, and acidification is carried out.
In the step (2), the crystallization temperature is 0-5 ℃.
Compared with the prior art, the invention has the following beneficial effects:
According to the invention, the crude ibuprofen sodium salt is purified in a recrystallization mode, ethanol is used as a poor solvent of the ibuprofen sodium salt to promote crystallization of the ibuprofen sodium salt on one hand, and is used as a good solvent of the rearrangement ester to extract the residual rearrangement ester in the crude ibuprofen sodium salt, so that the residual rearrangement ester in the crude ibuprofen sodium salt is removed, the rearrangement ester in the prepared crude ibuprofen is not detected, and the severe requirement of drug examination and evaluation on suspected genotoxic substance limit is met.
Detailed Description
The invention is further illustrated below with reference to examples. The raw materials used in the examples, unless otherwise specified, were all commercially available conventional raw materials; the process used in the examples, unless otherwise specified, is conventional in the art.
The crude ibuprofen sodium salt adopted in the example is crude ibuprofen sodium salt obtained by taking isobutylbenzene as a starting raw material and sequentially carrying out chloroketone, ketal, molecular rearrangement under catalysis, hydrolysis and crystallization, and the content of rearranged ester, namely alpha-methyl-4- (2-methylpropyl) phenylacetic acid-3-chloro-2, 2-dimethylpropyl ester, is 132ppm through detection.
The seed crystal adopted in the examples is ibuprofen sodium salt pure product (purity is more than or equal to 99.9%).
Example 1
A method for reducing the residual quantity of rearranged ester in the ibuprofen preparation process comprises the following steps:
(1) Taking a proper amount of crude ibuprofen sodium salt, completely dissolving in 70 ℃ water with the mass being 10 times that of the crude ibuprofen sodium salt, adding 10% of activated carbon with the mass being 10% of the crude ibuprofen sodium salt, controlling the temperature of the crude ibuprofen sodium salt solution at 70 ℃, keeping for 30min for decolorization, filtering, reducing the temperature of filtrate to below 40 ℃, adding 18 times of ethanol with the mass being 18 times that of the crude ibuprofen sodium salt, mixing and stirring for 10min, adding 1.5% of seed crystal with the mass being 1.5% of the crude ibuprofen sodium salt, continuing stirring for 10min, reducing the temperature to 0 ℃, standing until crystals are completely separated out, filtering, washing with ethanol, and obtaining recrystallized ibuprofen sodium salt;
(2) Completely dissolving the recrystallized ibuprofen sodium salt in water with the mass of 10 times, adding hydrochloric acid until the pH value of the system is lower than 2, cooling to 0 ℃ for crystallization, filtering to obtain crude ibuprofen, and detecting that the rearranged ester is not detected (detection limit is 1.6 ppm).
Example 2
A method for reducing the residual quantity of rearranged ester in the ibuprofen preparation process comprises the following steps:
(1) Taking a proper amount of crude ibuprofen sodium salt, completely dissolving in water with the mass of 11 times of 60 ℃, adding activated carbon with the mass of 8% of the crude ibuprofen sodium salt, controlling the temperature of a crude ibuprofen sodium salt solution at 60 ℃, keeping for 30min for decolorization, filtering, reducing the temperature of filtrate to below 40 ℃, adding ethanol with the mass of 15 times of the crude ibuprofen sodium salt, mixing and stirring for 15min, adding seed crystal with the mass of 2% of the crude ibuprofen sodium salt, continuing stirring for 15min, reducing the temperature to 5 ℃, standing until crystals are completely separated out, filtering, and washing with ethanol to obtain recrystallized ibuprofen sodium salt;
(2) Completely dissolving the recrystallized ibuprofen sodium salt in water with the mass of 9 times, adding hydrochloric acid until the pH value of the system is lower than 2, cooling to 2 ℃ for crystallization, filtering to obtain crude ibuprofen, and detecting that the rearranged ester is not detected (detection limit is 1.6 ppm).
Example 3
A method for reducing the residual quantity of rearranged ester in the ibuprofen preparation process comprises the following steps:
(1) Taking a proper amount of crude ibuprofen sodium salt, completely dissolving the crude ibuprofen sodium salt in water with the mass of 12 times of 80 ℃, adding active carbon with the mass of 5% of the crude ibuprofen sodium salt, controlling the temperature of a crude ibuprofen sodium salt solution at 80 ℃, keeping the temperature for 30min for decoloration, filtering, reducing the temperature of filtrate to below 40 ℃, adding ethanol with the mass of 20 times of the crude ibuprofen sodium salt, mixing and stirring for 5min, adding seed crystal with the mass of 1% of the crude ibuprofen sodium salt, continuing stirring for 5min, reducing the temperature to 10 ℃, standing until crystals are completely separated out, filtering, and washing with ethanol to obtain recrystallized ibuprofen sodium salt;
(2) Completely dissolving the recrystallized ibuprofen sodium salt in water with the mass of 8 times, adding hydrochloric acid until the pH value of the system is lower than 2, cooling to 5 ℃ for crystallization, filtering to obtain crude ibuprofen, and detecting that the rearranged ester is not detected (detection limit is 1.6 ppm).
Comparative example 1
This comparative example employs the method disclosed in example 1 of patent CN110590546 a. Although the rearrangement ester is not detected in the crude ibuprofen, the rearrangement ester needs to be subjected to secondary processing sodium hydroxide reflux reaction, and the energy consumption is high.
Claims (9)
1. A method for reducing the residual amount of rearranged ester in the ibuprofen preparation process, which is characterized in that: the method comprises the following steps:
(1) Completely dissolving crude ibuprofen sodium salt in 60-80 ℃ water, adding active carbon for decolorization, filtering, reducing the temperature of filtrate to below 40 ℃, adding ethanol, mixing and stirring, adding seed crystal, continuing stirring, reducing the temperature to 0-10 ℃, standing, filtering, and washing to obtain recrystallized ibuprofen sodium salt;
(2) Completely dissolving the recrystallized ibuprofen sodium salt in water, adding hydrochloric acid for acidification, crystallization and filtration to obtain crude ibuprofen;
the rearranged ester is alpha-methyl-4- (2-methylpropyl) phenylacetic acid-3-chloro-2, 2-dimethylpropyl ester, and the structural formula is as follows:
The content of rearrangement ester in the crude ibuprofen sodium salt is higher than 120ppm.
2. The method for reducing the residual amount of rearranged esters in the preparation of ibuprofen according to claim 1, wherein: in the step (1), the water consumption is 10-12 times of the mass of the crude ibuprofen sodium salt.
3. The method for reducing the residual amount of rearranged esters in the preparation of ibuprofen according to claim 1, wherein: in the step (1), the dosage of the activated carbon is 5-10% of the mass of the crude ibuprofen sodium salt; when the active carbon is decolorized, the temperature of the crude ibuprofen sodium salt solution is controlled to be 60-80 ℃.
4. The method for reducing the residual amount of rearranged esters in the preparation of ibuprofen according to claim 1, wherein: in the step (1), the dosage of the ethanol is 15-20 times of the mass of the crude ibuprofen sodium salt; adding ethanol, mixing and stirring for 5-15min.
5. The method for reducing the residual amount of rearranged esters in the preparation of ibuprofen according to claim 1, wherein: in the step (1), the seed crystal is pure ibuprofen sodium salt, and the dosage of the seed crystal is 1-2% of the mass of the crude ibuprofen sodium salt.
6. The method for reducing the residual amount of rearranged esters in the preparation of ibuprofen according to claim 1, wherein: in the step (1), after adding seed crystal, stirring is continued for 5-15min.
7. The method for reducing the residual amount of rearranged esters in the preparation of ibuprofen according to claim 1, wherein: in the step (2), the water is used in an amount which is 8 to 10 times the mass of the recrystallized ibuprofen sodium salt.
8. The method for reducing the residual amount of rearranged esters in the preparation of ibuprofen according to claim 1, wherein: in the step (2), hydrochloric acid is added until the pH value of the system is lower than 2, and acidification is carried out.
9. The method for reducing the residual amount of rearranged esters in the preparation of ibuprofen according to claim 1, wherein: in the step (2), the crystallization temperature is 0-5 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410333336.3A CN118239835A (en) | 2024-03-22 | 2024-03-22 | Method for reducing residual quantity of rearranged ester in ibuprofen preparation process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410333336.3A CN118239835A (en) | 2024-03-22 | 2024-03-22 | Method for reducing residual quantity of rearranged ester in ibuprofen preparation process |
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| Publication Number | Publication Date |
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| CN118239835A true CN118239835A (en) | 2024-06-25 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN202410333336.3A Pending CN118239835A (en) | 2024-03-22 | 2024-03-22 | Method for reducing residual quantity of rearranged ester in ibuprofen preparation process |
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| Country | Link |
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| CN (1) | CN118239835A (en) |
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- 2024-03-22 CN CN202410333336.3A patent/CN118239835A/en active Pending
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