CN117865766A - Environment-friendly preparation method of ibuprofen EP impurity R - Google Patents
Environment-friendly preparation method of ibuprofen EP impurity R Download PDFInfo
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- CN117865766A CN117865766A CN202410054145.3A CN202410054145A CN117865766A CN 117865766 A CN117865766 A CN 117865766A CN 202410054145 A CN202410054145 A CN 202410054145A CN 117865766 A CN117865766 A CN 117865766A
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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 79
- 239000012535 impurity Substances 0.000 title claims abstract description 78
- 229960001680 ibuprofen Drugs 0.000 title claims abstract description 77
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000002253 acid Substances 0.000 claims abstract description 18
- SQYNKIJPMDEDEG-UHFFFAOYSA-N paraldehyde Chemical compound CC1OC(C)OC(C)O1 SQYNKIJPMDEDEG-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229960003868 paraldehyde Drugs 0.000 claims abstract description 15
- 238000000746 purification Methods 0.000 claims abstract description 11
- KXUHSQYYJYAXGZ-UHFFFAOYSA-N isobutylbenzene Chemical compound CC(C)CC1=CC=CC=C1 KXUHSQYYJYAXGZ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 7
- 239000012074 organic phase Substances 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 238000010898 silica gel chromatography Methods 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 239000012295 chemical reaction liquid Substances 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 6
- 238000004821 distillation Methods 0.000 claims description 6
- 230000003472 neutralizing effect Effects 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 239000002274 desiccant Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 239000003480 eluent Substances 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 238000006386 neutralization reaction Methods 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical class [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 239000006227 byproduct Substances 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 9
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000003921 oil Substances 0.000 description 4
- 239000005457 ice water Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000001228 spectrum Methods 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
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 239000003599 detergent Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 238000002211 ultraviolet spectrum Methods 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001760 anti-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
- 239000002221 antipyretic Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 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
- 238000003908 quality control method Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses an environment-friendly preparation method of an ibuprofen EP impurity R, and belongs to the technical field of preparation of ibuprofen EP impurity standard substances. The preparation method of the invention comprises the following steps: the isobutylbenzene and the paraldehyde react under the action of acid to prepare the ibuprofen EP impurity R. The method has the advantages of simple operation, short preparation period, few byproducts, easy purification, high yield and environmental protection, and the prepared ibuprofen EP impurity R has high purity and can be used as an impurity standard.
Description
Technical Field
The invention relates to the technical field of preparation of ibuprofen EP impurity standard substances, in particular to an environment-friendly preparation method of ibuprofen EP impurity R.
Background
Ibuprofen (Ibuprofen), the name 2-4-isobutylphenyl propionic acid, chinese alias name anger wind, CAS:15687-27-1, the structural formula is:
ibuprofen is a non-steroidal anti-inflammatory drug widely used clinically, and belongs to aryl alkanoic acid drugs. Ibuprofen can be used as an alternative to aspirin, has stronger antipyretic, anti-inflammatory and analgesic effects, is mainly used for controlling inflammation and pain in cold, rheumatism, rheumatoid arthritis and other diseases, and has side effects which are much smaller than those of aspirin. The European pharmacopoeia, british pharmacopoeia, united states pharmacopoeia and Chinese pharmacopoeia all receive ibuprofen, and the determination of related substances is also described in detail.
There are 18 impurities reported in ibuprofen bulk drug, including impurities A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q and R. Ibuprofen EP impurity R, CAS:102120-87-6, the structural formula is as follows:
the ibuprofen EP impurity R is very important for quality control of bulk drugs, and a clear technical requirement is put forward for drug impurity research in drug quality research guidance in many countries, and an impurity standard product is obtained when the quality research is carried out. At present, no report exists on a preparation method of the ibuprofen EP impurity R.
Disclosure of Invention
In order to solve the defects in the prior art, the invention provides the environment-friendly preparation method of the ibuprofen EP impurity R, which has the advantages of simple operation, short preparation period, few byproducts, easy purification, high yield and environment protection, and the prepared ibuprofen EP impurity R has high purity.
The invention aims to achieve the aim, and the aim is achieved by the following technical scheme:
an environment-friendly preparation method of ibuprofen EP impurity R comprises the following steps:
the compound shown in the formula I reacts with the compound shown in the formula II under the action of acid to prepare the compound shown in the formula III.
The molar ratio of the compound shown in the formula I to the compound shown in the formula II to the acid is 1:0.25 to 0.5:0.5 to 2.
The compound shown in the formula I is isobutylbenzene, and the compound shown in the formula II is paraldehyde.
The acid is one of concentrated sulfuric acid, concentrated hydrochloric acid or trifluoroacetic acid; the molar concentration of the concentrated sulfuric acid is 9 mol/L-18.4 mol/L.
An environment-friendly preparation method of ibuprofen EP impurity R comprises the following steps:
step (1): firstly adding isobutylbenzene into a reaction vessel, stirring and cooling to-10 ℃ to 0 ℃, adding acid, then adding paraldehyde, heating to 5 ℃ to 10 ℃, and reacting for 2 hours to 4 hours under stirring to obtain a reaction liquid.
Specifically, firstly adding isobutylbenzene into a reaction vessel, stirring and cooling to-10 ℃ to 0 ℃, slowly dropwise adding acid into the system, and continuously stirring for 30 minutes while stirring; then adding the paraldehyde, wherein the paraldehyde can be dropwise added in batches, namely, after adding part of paraldehyde, stirring for a certain time (which can be 5 minutes), adding the rest part of paraldehyde; naturally heating to 5-10 ℃, and reacting for 2-4 hours under stirring to obtain a reaction liquid.
Step (2): after the reaction is finished, neutralizing the reaction liquid, extracting an organic phase, washing the organic phase, separating the liquid, and drying to obtain the crude ibuprofen EP impurity R.
Specifically, after the reaction is finished, slowly adding the reaction solution into ice water, adding a neutralizing agent, and neutralizing the reaction solution; the organic phase is then extracted by the addition of an extractant, preferably multiple extractions. Combining the extracted organic phases, washing the organic phases with a detergent, and separating the liquid; preferably, the washing may be performed multiple times. A desiccant is added to the organic phase to dry the organic phase, and a trace amount of water in the organic phase can be removed. The organic phase is concentrated to remove the solvent to obtain oily matter, namely the crude product of the ibuprofen EP impurity R.
Step (3): and purifying the crude ibuprofen EP impurity R to obtain pure ibuprofen EP impurity R.
The purification of the ibuprofen EP impurity R crude product comprises the following steps: and (3) carrying out reduced pressure distillation on the crude ibuprofen EP impurity R for 1-2 hours at 60-80 ℃, and purifying residues by silica gel column chromatography to obtain pure ibuprofen EP impurity R. Specifically, the crude ibuprofen EP impurity R is added into a single-mouth bottle, the single-mouth bottle is placed into an oil bath pot, reduced pressure distillation is carried out on the crude ibuprofen EP impurity R, the temperature is slowly heated to 60-80 ℃ and kept for 1-2 hours, distillate is removed, and the obtained residue is purified by silica gel column chromatography.
The neutralization reagent used in the neutralization reaction liquid is one of saturated sodium carbonate, saturated sodium bicarbonate and saturated sodium hydroxide.
The extractant used for extracting the organic phase is ethyl acetate or dichloromethane.
The washing agent used in the washing is saturated saline.
The drying agent used for drying is anhydrous sodium sulfate or anhydrous magnesium sulfate.
The eluent used for the silica gel column chromatography purification is pure petroleum ether.
Compared with the prior art, the invention has the beneficial effects that: the preparation method has the advantages of simple operation, short preparation period, few byproducts, easy purification, high yield and environmental protection, and the ibuprofen EP impurity R prepared by the method has high purity and no obvious impurity point.
Drawings
FIG. 1 is an MS spectrum of ibuprofen EP impurity R according to the present invention.
FIG. 2 is an illustration of the ibuprofen EP impurity R of the present invention 1 HNMR profile.
Fig. 3 is an HPLC profile of ibuprofen EP impurity R according to the present invention.
Fig. 4 is a UV spectrum of ibuprofen EP impurity R according to the present invention.
Fig. 5 is an IR spectrum of ibuprofen EP impurity R according to the present invention.
Fig. 6 is a graph of wavelengths corresponding to the peaks in fig. 5.
Detailed Description
The invention will be further described with reference to the accompanying drawings and specific embodiments. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. Further, it is understood that various changes or modifications of the invention may be made by those skilled in the art after reading the teachings of the invention, and such equivalents are intended to fall within the scope of the invention as defined in the application.
An environment-friendly preparation method of ibuprofen EP impurity R comprises the following steps:
the compound shown in the formula I reacts with the compound shown in the formula II under the action of acid to prepare the compound shown in the formula III. The compound shown in the formula I is isobutylbenzene, and the compound shown in the formula II is paraldehyde. The acid is one of concentrated sulfuric acid, concentrated hydrochloric acid or trifluoroacetic acid; the molar concentration of the concentrated sulfuric acid is 9 mol/L-18.4 mol/L. The molar ratio of the compound shown in the formula I to the compound shown in the formula II to the acid is 1:0.25 to 0.5:0.5 to 2. The method specifically comprises the following steps:
step (1): firstly adding isobutylbenzene into a reaction vessel, stirring and cooling to-10 ℃ to 0 ℃, slowly dropwise adding acid into the system, and continuously stirring for 30 minutes while stirring; then adding the paraldehyde, wherein the paraldehyde can be dropwise added in batches, namely, after adding part of paraldehyde, stirring for a certain time (which can be 5 minutes), adding the rest part of paraldehyde; naturally heating to 5-10 ℃, and reacting for 2-4 hours under stirring to obtain a reaction liquid.
Step (2): after the reaction is finished, slowly adding the reaction solution into ice water, and adding a neutralizing reagent, wherein the neutralizing reagent is one of saturated sodium carbonate, saturated sodium bicarbonate and saturated sodium hydroxide. Then adding an extractant for extracting the organic phase for multiple times, wherein the extractant is Ethyl Acetate (EA) or dichloromethane. Combining the extracted organic phases, washing the organic phases with a detergent saturated saline solution, and separating the organic phases; preferably, the washing may be performed multiple times. And adding a drying agent which is anhydrous sodium sulfate or anhydrous magnesium sulfate into the organic phase to dry the organic phase, so that trace moisture in the organic phase can be removed. The organic phase is concentrated to remove the solvent to obtain oily matter, namely the crude product of the ibuprofen EP impurity R.
Step (3): and (3) carrying out reduced pressure distillation on the crude ibuprofen EP impurity R for 1-2 hours at 60-80 ℃, and purifying residues by silica gel column chromatography to obtain the ibuprofen EP impurity R. Specifically, the crude ibuprofen EP impurity R is added into a single-mouth bottle, the single-mouth bottle is placed into an oil bath pot, reduced pressure distillation is carried out on the crude ibuprofen EP impurity R, the temperature is slowly heated to 60-80 ℃, the temperature is kept for 1-2 hours, distillate is removed, the obtained residue is purified by silica gel column chromatography, and the pure ibuprofen EP impurity R is obtained, and the eluent used for the silica gel column chromatography purification is pure petroleum ether.
Example 1
The environment-friendly preparation method of the ibuprofen EP impurity R comprises the following steps:
isobutylbenzene (5 mL,32.11 mmol) was added to a 100mL single-necked flask, and the flask was stirred and cooled to-10℃to slowly add concentrated sulfuric acid (1.3 mL,24.31mmol, mass fraction of concentrated sulfuric acid: about 98% and molar concentration: about 18.4 mol/L) dropwise to the system, followed by stirring for 30 minutes, then by adding paraldehyde (0.25 mL,9.17 mmol) in portions, and after the completion of the dropwise addition, the temperature was naturally raised to 5℃and stirring was continued for 3 hours to obtain a reaction solution. After the reaction was completed, the reaction solution was slowly added to ice water (100 mL), neutralized with saturated sodium carbonate, then extracted with EA (50 mL), repeated 3 times, the organic phases were combined, washed with saturated brine (50 mL), repeated 3 times, separated, dried over anhydrous sodium sulfate, and concentrated to remove the solvent to give an oil, which was ibuprofen EP impurity R crude product.
Adding the crude ibuprofen EP impurity R into a 100mL single-mouth bottle, placing the single-mouth bottle into an oil bath pot, performing reduced pressure distillation on the crude ibuprofen EP impurity R, slowly heating to 60 ℃, keeping the temperature for 1 hour, removing distillate, and purifying the obtained residue by silica gel column chromatography, wherein the eluent is as follows: pure petroleum ether gave 7.75g of colorless oil as pure ibuprofen EP impurity R in 82% yield and 95.01% purity.
Example 2
The difference from example 1 is that the acid used is sulfuric acid (3.4 mL,30.6 mmol) at a molar concentration of 9 mol/L.
Pure ibuprofen EP impurity R: the yield was 70% and the purity was 96.06%.
Example 3
The difference from example 1 is that the acid used is concentrated hydrochloric acid (2.7 mL,32.11 mmol).
The concentrated hydrochloric acid in this example 3 may be commercially available 36 to 38% by mass, and the molar concentration is about 12mol/L.
Pure ibuprofen EP impurity R: the yield was 75% and the purity was 95.28%.
Example 4
The difference from example 1 is that the acid used is trifluoroacetic acid (2.45 mL,32.11 mmol).
Pure ibuprofen EP impurity R: the yield was 70% and the purity was 95.00%.
Ibuprofen EP impurity R has the formula: c (C) 22 H 30 ；
Molecular weight of ibuprofen EP impurity R: 294.23.
the pure product of the ibuprofen EP impurity R prepared by the method of the present invention was characterized as represented by example 1, and the characterization results of the pure product of the ibuprofen EP impurity R prepared in other examples were consistent with example 1, and are not provided.
The pure product of the ibuprofen EP impurity R obtained after purification is analyzed by a mass spectrometer, an MS spectrum is shown in figure 1, and in the MS spectrum, the peak of M/z= 294.28 is a molecular ion peak M+H of the ibuprofen EP impurity R, and the molecular weight of the ibuprofen EP impurity R is matched.
Analyzing the purified pure ibuprofen EP impurity R by using a nuclear magnetic resonance spectrometer, wherein the pure ibuprofen EP impurity R is obtained by using a nuclear magnetic resonance spectrometer 1 The HNMR profile is shown in figure 2, 1 HNMR(600MHz，CDC l3 )，δ7.14(d，4H)，7.07(s，4H)，4.11(m，1H)，2.45(d，2H)，1.84(m，2H)，1.65(d，1H)，0.9(d，4H)。
the purified pure product of the ibuprofen EP impurity R is analyzed by a high performance liquid chromatograph, wherein the HPLC is shown in figure 3, the peak time of the impurity R is 65.350min, and the purity is 95.01%.
The pure product of the ibuprofen EP impurity R obtained after purification is analyzed by an ultraviolet detector, the UV spectrum of the pure product is shown as figure 4, and the UV shows an absorption peak at 225.93 nm.
The pure product of the ibuprofen EP impurity R obtained after purification is analyzed by an infrared detector, the IR spectrum of the pure product is shown in figure 5, and the wavelengths corresponding to the peaks are shown in figure 6.
Claims (8)
1. An environment-friendly preparation method of ibuprofen EP impurity R is characterized by comprising the following steps:
the compound shown in the formula I reacts with the compound shown in the formula II under the action of acid to prepare the compound shown in the formula III.
2. The environment-friendly preparation method of the ibuprofen EP impurity R, which is disclosed in claim 1, is characterized in that the molar ratio of the compound shown in the formula I to the compound shown in the formula II to the acid is 1:0.25 to 0.5:0.5 to 2.
3. The environment-friendly preparation method of ibuprofen EP impurity R according to claim 1, wherein the compound shown in the formula I is isobutylbenzene, and the compound shown in the formula II is paraldehyde.
4. The method for the environmentally friendly preparation of ibuprofen EP impurity R according to claim 1, wherein said acid is one of concentrated sulfuric acid, concentrated hydrochloric acid or trifluoroacetic acid.
5. The method for the environmentally friendly preparation of ibuprofen EP impurity R according to claim 3, which is characterized by comprising the following steps:
firstly adding isobutylbenzene into a reaction vessel, stirring and cooling to-10 ℃ to 0 ℃, adding acid, then adding paraldehyde, heating to 5 ℃ to 10 ℃, and reacting for 2 hours to 4 hours under stirring to obtain a reaction solution;
after the reaction is finished, neutralizing the reaction liquid, extracting an organic phase, washing the organic phase, separating the liquid, and drying to obtain an ibuprofen EP impurity R crude product;
and purifying the crude ibuprofen EP impurity R to obtain pure ibuprofen EP impurity R.
6. The environment-friendly preparation method of the ibuprofen EP impurity R according to claim 5, wherein the purification of the ibuprofen EP impurity R crude product comprises the following steps: and (3) carrying out reduced pressure distillation on the crude ibuprofen EP impurity R for 1-2 hours at 60-80 ℃, and purifying residues by silica gel column chromatography to obtain pure ibuprofen EP impurity R.
7. The environment-friendly preparation method of ibuprofen EP impurity R according to claim 5, wherein the neutralization reagent used in the neutralization reaction liquid is one of saturated sodium carbonate, saturated sodium bicarbonate and saturated sodium hydroxide;
the extractant used for extracting the organic phase is ethyl acetate or dichloromethane;
the washing agent used for washing is saturated saline water;
the drying agent used for drying is anhydrous sodium sulfate or anhydrous magnesium sulfate.
8. The method for preparing ibuprofen EP impurity R according to claim 5, wherein the eluent used for the silica gel column chromatography purification is pure petroleum ether.
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