CN111205151A - Environment-friendly preparation method of ibuprofen impurity I - Google Patents
Environment-friendly preparation method of ibuprofen impurity I Download PDFInfo
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- CN111205151A CN111205151A CN202010132728.5A CN202010132728A CN111205151A CN 111205151 A CN111205151 A CN 111205151A CN 202010132728 A CN202010132728 A CN 202010132728A CN 111205151 A CN111205151 A CN 111205151A
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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 179
- 229960001680 ibuprofen Drugs 0.000 title claims abstract description 172
- 239000012535 impurity Substances 0.000 title claims abstract description 140
- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 39
- 238000001514 detection method Methods 0.000 claims abstract description 33
- 238000004440 column chromatography Methods 0.000 claims abstract description 20
- 238000000746 purification Methods 0.000 claims abstract description 20
- 238000003756 stirring Methods 0.000 claims abstract description 16
- 238000000926 separation method Methods 0.000 claims abstract description 13
- 239000000126 substance Substances 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 238000001704 evaporation Methods 0.000 claims abstract description 4
- 238000001914 filtration Methods 0.000 claims abstract description 3
- OUCSEDFVYPBLLF-KAYWLYCHSA-N 5-(4-fluorophenyl)-1-[2-[(2r,4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-n,4-diphenyl-2-propan-2-ylpyrrole-3-carboxamide Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@H]2OC(=O)C[C@H](O)C2)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 OUCSEDFVYPBLLF-KAYWLYCHSA-N 0.000 claims description 45
- 150000001875 compounds Chemical class 0.000 claims description 40
- 239000003480 eluent Substances 0.000 claims description 17
- 238000011084 recovery Methods 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 19
- 239000013558 reference substance Substances 0.000 abstract description 12
- 239000006227 byproduct Substances 0.000 abstract description 7
- 238000011160 research Methods 0.000 abstract description 7
- 230000007613 environmental effect Effects 0.000 abstract description 6
- 239000000243 solution Substances 0.000 description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 18
- 239000012295 chemical reaction liquid Substances 0.000 description 14
- 239000000523 sample Substances 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 238000002390 rotary evaporation Methods 0.000 description 13
- 239000000203 mixture Substances 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- 239000012088 reference solution Substances 0.000 description 7
- 239000012085 test solution Substances 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000003908 quality control method Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- VLSOAXRVHARBEQ-UHFFFAOYSA-N [4-fluoro-2-(hydroxymethyl)phenyl]methanol Chemical compound OCC1=CC=C(F)C=C1CO VLSOAXRVHARBEQ-UHFFFAOYSA-N 0.000 description 3
- 150000001793 charged compounds Chemical class 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 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
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 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
- 238000011002 quantification Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
- C07C1/20—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from organic compounds containing only oxygen atoms as heteroatoms
- C07C1/207—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from organic compounds containing only oxygen atoms as heteroatoms from carbonyl compounds
- C07C1/2076—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from organic compounds containing only oxygen atoms as heteroatoms from carbonyl compounds by a transformation in which at least one -C(=O)- moiety is eliminated
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C15/00—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts
- C07C15/12—Polycyclic non-condensed hydrocarbons
- C07C15/16—Polycyclic non-condensed hydrocarbons containing at least two phenyl groups linked by one single acyclic carbon atom
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/69—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to carbon-to-carbon double or triple bonds
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- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
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Abstract
The invention provides an environment-friendly preparation method of ibuprofen impurity I, belonging to the technical field of preparation of pharmaceutical impurity standard products, and comprising the following steps: adding NH to EtOH solution containing ibuprofen impurities H and Zn4And (3) reacting Cl and HCl for 10-15h at 50-90 ℃ under stirring, filtering, evaporating the solvent, and performing column chromatography separation and purification to obtain ibuprofen impurity I. The method has simple operationThe method has the advantages of short preparation period, few byproducts, easiness in purification, high yield and environmental friendliness, the prepared ibuprofen impurity I is high in purity, has no obvious impurity point, meets the requirements of impurity reference substances, can be used as an ibuprofen impurity I standard substance, is applied to qualitative and quantitative research and detection of the ibuprofen impurity I, and can improve the accuracy of the detection method.
Description
Technical Field
The invention belongs to the technical field of preparation of pharmaceutical impurity standard products, and particularly relates to an environment-friendly preparation method of ibuprofen impurity I.
Background
Ibuprofen (Ibuprofen) with the chemical name of 2- (4-isobutylphenyl) propionic acid is a widely used non-steroidal anti-inflammatory drug in clinic, belonging to aryl alkanoic acid drugs. Ibuprofen can be used as a substitute of aspirin, has stronger antipyretic, anti-inflammatory and analgesic effects, is mainly used for controlling inflammation and pain in diseases such as cold, rheumatism, rheumatoid arthritis and the like, and has much smaller side effect than aspirin. The European pharmacopoeia, British pharmacopoeia, United states pharmacopoeia, pharmacopoeia and Chinese pharmacopoeia all contain ibuprofen, and the determination of related substances is elaborated in detail. There are 18 impurities reported in ibuprofen drug substance, including, impurities A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q and R. Impurities are very important for quality control of raw material medicines, and many countries put forward clear technical requirements on medicine impurity research in medicine quality research guidance and obtain impurity standard products during quality research. At present, the preparation method of the ibuprofen impurity I is not reported, and particularly the preparation method of the high-purity ibuprofen impurity I.
Disclosure of Invention
The invention aims to provide the environment-friendly preparation method of the ibuprofen impurity I, which has the advantages of simple operation, short preparation period, less byproducts, easiness in purification, high yield and environment friendliness, and the prepared ibuprofen impurity I has high purity and no obvious impurity point.
The technical scheme adopted by the invention for realizing the purpose is as follows:
an environment-friendly preparation method of ibuprofen impurity I comprises the following steps:
adding NH to EtOH solution containing ibuprofen impurities H and Zn4And (3) reacting Cl and HCl for 10-15h at 50-90 ℃ under stirring, filtering, evaporating the solvent, and performing column chromatography separation and purification to obtain ibuprofen impurity I.
The method has the advantages of simple operation, short preparation period, few byproducts, easy purification, high yield and environmental protection, the prepared ibuprofen impurity I has high purity and no obvious impurity point, meets the requirements of impurity reference substances, can be used as an ibuprofen impurity I standard substance, is applied to qualitative and quantitative research and detection of the ibuprofen impurity I, and has certain significance on quality control of the ibuprofen and related preparations thereof.
Preferably, ibuprofen impurities H, Zn and NH4The molar ratio of Cl is 1:2: 2.5-3.5.
Preferably, the ratio of ibuprofen impurities H to HCl is 1:1.5-2.0(g/mL)
Preferably, the eluent for column chromatography separation and purification is PE: EA ═ 10-30: 1.
Preferably, the yield of the profen impurity I is at least 85.00%.
Preferably, the profen impurity H is prepared by the following method:
step 1: a compound shown as a formula (I) and a compound shown as a formula (II) are mixed in NaOC2H5Under the catalytic action of the compound (III), the compound shown in the formula (III) is prepared;
step 2: the compound of formula (III) is in CH3And reacting in the presence of MgBr to obtain ibuprofen impurity H. The preparation method of the ibuprofen impurity H has the advantages of simple operation, short preparation period, few byproducts, easy purification, high yield and environmental protection, and the prepared ibuprofen impurity H has high purity and no obvious impurity point.
The invention further aims to provide an ibuprofen impurity I, which is prepared by the environment-friendly preparation method.
Preferably, the purity of the profen impurity I is at least 99.00%.
Still another object of the present invention is to provide a method for detecting ibuprofen impurity I, wherein the standard substance is the ibuprofen impurity I as claimed in claim 7 or 8. The ibuprofen impurity I has higher purity, and the accuracy of the detection method can be improved.
Preferably, the detection method has good accuracy, the average recovery rate of the ibuprofen impurity I is at least 99.90 percent, and the RSD percent is less than or equal to 5 percent.
Compared with the prior art, the invention has the beneficial effects that: the method has the advantages of simple operation, short preparation period, few byproducts, easy purification, high yield and environmental protection, the prepared ibuprofen impurity I has high purity and no obvious impurity point, meets the requirements of impurity reference substances, can be used as an ibuprofen impurity I standard substance, is applied to qualitative and quantitative research and detection of the ibuprofen impurity I, and has certain significance on quality control of the ibuprofen and related preparations thereof. The ibuprofen impurity I has higher purity, and the accuracy of the detection method can be improved when the ibuprofen impurity I is used as a standard substance of the ibuprofen impurity I for detection.
The invention adopts the technical scheme to provide the environment-friendly preparation method of the ibuprofen impurity I, overcomes the defects of the prior art, and has reasonable design and convenient operation.
Drawings
FIG. 1 is a MS spectrum of ibuprofen impurity H in example 1 of the present invention;
FIG. 2 shows ibuprofen impurity H in example 1 of the present invention1HNMR spectrogram;
FIG. 3 is an HPLC chromatogram of ibuprofen impurity H in example 1 of the present invention
FIG. 4 is a MS spectrum of ibuprofen impurity I in example 1 of the present invention;
FIG. 5 shows ibuprofen impurity I in example 1 of the present invention1HNMR spectrogram;
figure 6 is an HPLC profile of ibuprofen impurity I in example 1 of the present invention.
Detailed Description
While the invention is susceptible to various modifications and alternative forms, specific embodiments thereof have been shown by way of example in the drawings and are herein described in detail. It is not intended to limit the invention to the particular form disclosed, but on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention as defined by the appended claims.
These examples are provided only for more specifically illustrating the present invention, and it is apparent to those skilled in the art that the scope of the present invention is not limited to these examples according to the gist of the present invention.
An embodiment of the invention provides an environment-friendly preparation method of ibuprofen impurity I, which comprises the following synthetic route:
the method specifically comprises the following steps:
adding NH to EtOH solution containing ibuprofen impurities H and Zn4Cl and HCl, ibuprofen impurities H, Zn and NH4The mol ratio of Cl is 1:2:2.5-3.5, the dosage ratio of ibuprofen impurity H and HCl is 1:1.5-2.0(g/mL), then the mixture is stirred and reacted for 10-15H at 50-90 ℃, the solvent is filtered and evaporated, and the mixture is separated and purified by column chromatography, and the eluent PE: EA is 10-30:1, thus obtaining ibuprofen impurity I.
The preparation method provided by the implementation method has the advantages of simplicity in operation, short preparation period, few byproducts, easiness in purification, high yield and environmental friendliness, the yield of the ibuprofen impurity I is at least 85.00%, the purity of the prepared ibuprofen impurity I is high, no obvious impurity point exists, the requirements of an impurity reference substance are met, the ibuprofen impurity I can be used as an ibuprofen impurity I standard substance and applied to qualitative and quantitative research and detection of the ibuprofen impurity I, and certain significance is realized on quality control of ibuprofen and related preparations of the ibuprofen.
In one embodiment of the invention, the lofen impurity H is prepared by the following method:
step 1: adding the compound shown in the formula (I) and the compound shown in the formula (II) into an EtOH solution at 60-80 ℃ in batchesNaOC2H5A compound of formula (I), a compound of formula (II) and NaOC2H5The molar ratio of the compound to the solvent is 1:1:1.5-2.3, the reaction is stirred for 10-15h, the reaction liquid is subjected to rotary evaporation to remove EtOH, the obtained solid is dissolved, and the obtained solid is separated and purified by column chromatography, wherein the eluent is PE: EA which is 5-15:1, and the compound shown in the formula (III) is obtained;
step 2: dissolving the compound shown in the formula (III) in anhydrous THF, and slowly adding CH with the concentration of 1mol/L at-10 to-30 DEG C3MgBr reagent, compound of formula (III) and CH3And (3) stirring and reacting the MgBr at the molar ratio of 1:1 for 40-80min at the temperature, performing rotary evaporation on the reaction liquid to remove THF, and separating and purifying by column chromatography, wherein an eluent is PE: EA: 40-60:1, so as to obtain ibuprofen impurity H. The preparation method of the ibuprofen impurity H has the advantages of simple operation, short preparation period, few byproducts, easiness in purification, high yield and environmental friendliness, the yield of the ibuprofen impurity H is at least 35.00%, the purity of the prepared ibuprofen impurity H is at least 99.00%, and no obvious impurity point exists, so that the yield and the purity of the ibuprofen impurity I are improved.
The embodiment of the invention also provides an ibuprofen impurity I, which is prepared by the environment-friendly preparation method.
In one embodiment of the invention, the purity of the profen impurity I is at least 99.00%.
The embodiment of the invention also provides a method for detecting the ibuprofen impurity I, which adopts an HPLC method and specifically comprises the following steps:
(1) preparing a test solution: weighing a proper amount of ibuprofen raw material, precisely weighing, adding 50% acetonitrile solution for dissolving, and quantitatively diluting to prepare a solution containing 2mg of ibuprofen per 1mL as a test solution;
(2) preparing a reference substance solution: taking a proper amount of the ibuprofen impurity I, precisely weighing, adding 50% acetonitrile solution for dissolving, and quantitatively diluting to prepare a solution containing 2.0 mu g of the ibuprofen impurity I per 1mL, wherein the solution is used as a reference solution; the ibuprofen impurity I has higher purity, so that the accuracy of the detection method can be improved;
(3) sample detection: precisely measuring the sample solution and the reference solution by 50 μ L, respectively, injecting into a liquid chromatograph, and recording chromatogram; wherein, the chromatographic conditions are as follows: a chromatographic column: agilent EC-C184.6X 150mm 2.7 μm; flow rate: 1.0 mL/min; detection wavelength: 254 nm; sample introduction amount: 5 mu L of the solution; column temperature: 25 ℃; mobile phase: a: 20% acetonitrile; b: 0.1% phosphoric acid solution.
In one embodiment of the invention, the detection method has good accuracy, the average recovery rate of the ibuprofen impurity I is at least 99.90%, and the RSD is less than or equal to 5%.
The invention is further illustrated by the following examples. It should be understood that the examples are for illustrative purposes only and are not intended to limit the scope and spirit of the present invention.
Example 1:
the synthetic route of the ibuprofen impurity I is as follows:
an environment-friendly preparation method of ibuprofen impurity I comprises the following steps:
1) the preparation method of the ibuprofen impurity H comprises the following specific steps:
step 1: 0.5g of the compound of the formula (I) and 0.543g of the compound of the formula (II) are mixed and dissolved in EtOH, and 0.42g of NaOC is then dissolved at 60-80 DEG.C2H5Adding the raw materials into the mixture in 4 batches, stirring the mixture for reaction for 12 hours, carrying out rotary evaporation on the reaction liquid to remove EtOH, dissolving the obtained solid, and carrying out column chromatography separation and purification on the solid, wherein an eluent is PE, EA is 10:1, so as to obtain the compound shown in the formula (III);
step 2: 0.5g of the compound represented by the formula (III) was dissolved in anhydrous THF, and 1.56mL of 1mol/L CH was slowly added thereto at-20 ℃3MgBr reagent, compound of formula (III) and CH3The molar ratio of MgBr is 1:1, stirring and reacting are carried out for 60min at the temperature, THF is removed by rotary evaporation of reaction liquid, and the reaction liquid is separated and purified by column chromatography, the eluent is PE: EA is 50:1, 200mg of ibuprofen impurity H is obtained, and the yield of the ibuprofen impurity H is 38.10%;
2) preparation of ibuprofen impurity I to a concentration of 0.3g ibuprofen impurity0.143g NH was added to an EtOH solution of proton H and 0.116g Zn4And (3) stirring and reacting Cl and 0.5mL of HCl at 70 ℃ for 12h, after the reaction result, performing rotary evaporation on the reaction liquid to remove EtOH, dissolving the obtained solid, and performing column chromatography separation and purification, wherein the eluent is PE (ethylene oxide) EA: 20:1, so that 254mg of ibuprofen impurity I is obtained, and the yield of the ibuprofen impurity I is 86.00%.
The structural formula of ibuprofen impurity H is:
molecular formula of ibuprofen impurity H: c24H32O；
Molecular weight of ibuprofen impurity H: 336.51.
and (3) analyzing the synthesis product ibuprofen impurity H by using a mass spectrometer, wherein an MS spectrogram is shown in figure 1, and in the mass spectrogram, a peak with the m/z being 337.1 is a molecular ion peak of the ibuprofen impurity H and is consistent with the molecular weight of the ibuprofen impurity H. Meanwhile, the chromatogram and mass spectrum peak of the compound shown in the formula (III) as the raw material are not shown on the spectrogram, which indicates that the conversion rate reaches 100 percent.
Analyzing the synthesis product ibuprofen impurity H by using a nuclear magnetic resonance apparatus, and the method1The HNMR spectrum is shown in figure 2,1HNMR(400MHz,DMSO-d6):δ7.85-7.87(d,2H,Ar-H),7.26-7.28(d,2H,Ar-H),7.18-7.20(d,2H,Ar-H),7.03-7.05(d,2H,Ar-H),3.19-3.33(m,3H,CH,CH2),2.50-2.54(d,2H,CH2),2.37-2.39(d,2H,CH2),1.74-1.84(m,2H,CH),1.21-1.22(d,3H,CH3),0.83-0.86(d,12H,CH3)。
the purity analysis of the ibuprofen impurity H of the synthesized product adopts an HPLC detection method, and the conditions of the HPLC detection method are as follows: a chromatographic column: agilent EC-C184.6X 150mm 2.7 μm; flow rate: 0.3 mL/min; detection wavelength: sig 254 nm; sample introduction amount: 5 mu L of the solution; column temperature: 25 ℃; mobile phase: a: 95% acetonitrile; b: 0.1% formic acid solution; gradient elution procedure as per table 1; time: and (4) 18 min. Fig. 3 is an HPLC chromatogram of the synthetic product ibuprofen impurity H, and the analysis results of each peak in the HPLC chromatogram are shown in table 2, and it can be seen that the purity of the synthetic product ibuprofen impurity H is 99.64%.
Table 1 flow phase ratio example
| Time(Min) | A(％) | B(％) |
| 0.00 | 95 | 5 |
| 18.00 | 95 | 5 |
TABLE 2 analysis of peaks in HPLC chromatogram
| Peak# | RetTime(min) | Area | | Area％ | |
| 1 | 0.753 | 6.47676 | 2.07981 | 0.0405 | |
| 2 | 0.936 | 13.37398 | 3.09745 | 0.0836 | |
| 3 | 1.294 | 18.22627 | 4.02625 | 0.1140 | |
| 4 | 4.363 | 18.83100 | 2.07588 | 0.1178 | |
| 5 | 4.926 | 1.59354e4 | 1673.86853 | 99.6442 | |
| Totals | 1.59923e4 | 1685.14792 | 100.0000 |
The structural formula of ibuprofen impurity I is:
the molecular formula of ibuprofen impurity I: c24H34；
Molecular weight of ibuprofen impurity I: 322.24.
analyzing the synthesis product ibuprofen impurity I by a mass spectrometer, wherein an MS spectrogram of the synthesis product ibuprofen impurity I is shown in figure 4, and in the mass spectrogram, a peak with m/z being 321.3 is a molecular ion peak of the ibuprofen impurity I and is consistent with the molecular weight of the ibuprofen impurity I; the peak with m/z being 336.6 is the molecular ion peak of ibuprofen impurity H, and is consistent with the molecular weight of ibuprofen impurity I.
Analyzing the synthesized product ibuprofen impurity I by using a nuclear magnetic resonance apparatus, and the method1The HNMR spectrum is shown in figure 5,1HNMR(400MHz,DMSO-d6):δ7.09-7.13(d,4H,Ar-H),7.03-7.07(d,4H,Ar-H),2.50-2.51(m,1H,CH),2.38-2.40(d,6H,CH2),1.79-1.82(m,4H,CH,CH2),1.19-1.21(d,3H,CH3),0.83-0.87(d,12H,CH3)。
the purity analysis of the ibuprofen impurity I of the synthetic product adopts an HPLC detection method, and the conditions of the HPLC detection method are as follows: a chromatographic column: agilent EC-C184.6X 150mm 2.7 μm; flow rate: 0.3 mL/min; detection wavelength: sig 254 nm; sample introduction amount: 5 mu L of the solution; column temperature: 25 ℃; mobile phase: a: 20% acetonitrile; b: 0.1% phosphoric acid solution; gradient elution procedure as per table 3; time: and (5) 42 min. Fig. 6 is an HPLC chromatogram of the synthesized product ibuprofen impurity I, and the analysis results of each peak in the HPLC chromatogram are shown in table 4, and it can be seen that the purity of the synthesized product ibuprofen impurity I is 99.76%.
TABLE 3 proportion of mobile phase
| Time(Min) | A(％) | B(％) |
| 0.00 | 20 | 80 |
| 18.00 | 20 | 80 |
| 20.00 | 90 | 10 |
| 40.00 | 90 | 10 |
| 42.00 | 20 | 80 |
TABLE 4 analysis of peaks in HPLC chromatogram
| Peak# | RetTime(min) | Area | | Area％ | |
| 1 | 21.653 | 8.25082 | 2.29333 | 0.2440 | |
| 2 | 22.637 | 3373.52539 | 1059.22314 | 99.7560 | |
| Totals | 3381.77621 | 1061.51648 | 100.0000 |
Example 2:
an environment-friendly preparation method of ibuprofen impurity I comprises the following steps:
1) the preparation method of the ibuprofen impurity H comprises the following specific steps:
step 1: 0.5g of the compound of the formula (I) and 0.543g of the compound of the formula (II) are mixed and dissolved in EtOH, and 0.315g of NaOC are then added at 60-80 DEG C2H5Adding the mixture into the mixture in 4 batches, stirring the mixture for reaction for 15 hours, removing EtOH from the reaction solution by rotary evaporation, dissolving the obtained solid, and separating and purifying the solid by column chromatography, wherein an eluent is PE, EA is 8:1, and the compound shown in the formula (III) is obtained;
step 2: 0.5g of the compound represented by the formula (III) was dissolved in anhydrous THF, and 1.56mL of 1mol/L CH was slowly added thereto at-20 ℃3MgBr reagent, compound of formula (III) and CH3MgBr at 1:1 molar ratio, stirring at the temperature for 60min, evaporating the reaction solution to remove THF, and purifying by column chromatography with PE: EA: 40:1 eluent to obtain 194mg ibuprofenThe yield of ibuprofen impurity H was 37.02%, with a purity of 99.27%.
2) Preparation of ibuprofen impurity I, 0.130g NH was added to an EtOH solution containing 0.3g ibuprofen impurity H and 0.116g Zn4And (3) carrying out a reaction of Cl and 0.45mL of HCl at 70 ℃ for 12h under stirring, carrying out rotary evaporation on the reaction liquid after the reaction result to remove EtOH, dissolving the obtained solid, and carrying out column chromatography separation and purification, wherein the eluent is PE: EA: 20:1, so that 252mg of ibuprofen impurity I is obtained, the yield of the ibuprofen impurity I is 85.13%, and the purity is 99.32%.
Example 3:
an environment-friendly preparation method of ibuprofen impurity I comprises the following steps:
1) the preparation method of the ibuprofen impurity H comprises the following specific steps:
step 1: 0.5g of the compound of the formula (I) and 0.543g of the compound of the formula (II) are mixed and dissolved in EtOH, and 0.42g of NaOC is then dissolved at 60-80 DEG.C2H5Adding the raw materials into the mixture in 4 batches, stirring the mixture for reaction for 12 hours, carrying out rotary evaporation on the reaction liquid to remove EtOH, dissolving the obtained solid, and carrying out column chromatography separation and purification on the solid, wherein an eluent is PE, EA is 10:1, so as to obtain the compound shown in the formula (III);
step 2: 0.5g of the compound represented by the formula (III) was dissolved in anhydrous THF, and 1.56mL of 1mol/L CH was slowly added thereto at-20 ℃3MgBr reagent, and L-cysteine hydrochloride, a compound represented by the formula (III) and CH3The molar ratio of MgBr is 1:1, stirring and reacting are carried out for 60min at the temperature, THF is removed by rotary evaporation from reaction liquid, and separation and purification are carried out by column chromatography, the eluent is PE: EA is 50:1, 230mg of ibuprofen impurity H is obtained, the yield of the ibuprofen impurity H is 53.78%, and the purity is 99.73%; the yield of ibuprofen impurity H, the target product of this example, was improved compared to example 1, probably because the introduction of L-cysteine hydrochloride increased the Grignard reagent CH3The yield and selectivity of the reaction of MgBr and the compound (unsaturated carbonyl compound) shown in the formula (III) effectively inhibit the occurrence of side reaction and reduce the production of alcohol products, so that the yield of the target product, namely ibuprofen impurity H is improved, and the L-cysteine hydrochloride has the advantages of low price and pollution reduction;
2) preparation of ibuprofen impurity I, 0.143g NH was added to an EtOH solution containing 0.3g ibuprofen impurity H and 0.116g Zn4And (3) stirring Cl and 0.5mL of HCl at 70 ℃ for reaction for 12h, after the reaction result, performing rotary evaporation on the reaction liquid to remove EtOH, dissolving the obtained solid, and performing column chromatography separation and purification, wherein an eluent is PE (ethylene oxide) EA: 20:1 to obtain 255mg of ibuprofen impurity I, the yield of the ibuprofen impurity I is 86.34%, and the purity is 99.81%.
Example 4:
an environment-friendly preparation method of ibuprofen impurity I comprises the following steps:
1) the preparation method of the ibuprofen impurity H comprises the following specific steps:
step 1: 0.5g of the compound of the formula (I) and 0.543g of the compound of the formula (II) are mixed and dissolved in EtOH, and 0.42g of NaOC is then dissolved at 60-80 DEG.C2H5Adding the raw materials into the mixture in 4 batches, stirring the mixture for reaction for 12 hours, carrying out rotary evaporation on the reaction liquid to remove EtOH, dissolving the obtained solid, and carrying out column chromatography separation and purification on the solid, wherein an eluent is PE, EA is 10:1, so as to obtain the compound shown in the formula (III);
step 2: 0.5g of the compound represented by the formula (III) was dissolved in anhydrous THF, and 1.56mL of 1mol/L CH was slowly added thereto at-20 ℃3MgBr reagent, compound of formula (III) and CH3The molar ratio of MgBr is 1:1, stirring and reacting are carried out for 60min at the temperature, THF is removed by rotary evaporation of reaction liquid, and the reaction liquid is separated and purified by column chromatography, the eluent is PE: EA is 50:1, 200mg of ibuprofen impurity H is obtained, and the yield of the ibuprofen impurity H is 38.10%;
2) preparation of ibuprofen impurity I, 0.143g NH was added to an EtOH solution containing 0.3g ibuprofen impurity H and 0.116g Zn4And stirring Cl, 1.53mg of triethylamine and 0.5mL of HCl at 70 ℃ for reaction for 12 hours, after the reaction result, performing rotary evaporation on the reaction liquid to remove EtOH, dissolving the obtained solid, and performing column chromatography separation and purification, wherein an eluent is PE, EA is 20:1, so that 266mg of ibuprofen impurity I is obtained, the yield of the ibuprofen impurity I is 90.11%, and the purity is 99.86%. The yield of ibuprofen impurity I, the target product of this example, was improved over example 1, probably because the addition of triethylamine increased the ibuprofen impurities H plusThe hydrogen is the activity and selectivity of the ibuprofen impurity I, the conversion rate of catalytic hydrogenation of an aromatic ring is reduced, the hydrogenation conversion rate of C ═ O double bonds in the ibuprofen impurity H is improved, a large amount of the ibuprofen impurity H is hydrogenated and converted into the ibuprofen impurity I, and therefore the yield of the target product ibuprofen impurity I is improved.
Example 5:
a method for detecting ibuprofen impurity I specifically comprises the following steps:
(1) preparing a test solution: accurately weighing 20mg of ibuprofen raw material, adding 10mL of 50% acetonitrile solution for dissolving to obtain a sample solution;
(2) preparing a reference substance solution: accurately weighing 20 mu g of ibuprofen impurity I obtained in the example 1, adding 10mL of 50% acetonitrile solution for dissolving, and taking the solution as a reference solution;
(3) sample detection: precisely measuring the sample solution and the reference solution at 50 μ L, respectively, and injecting into a liquid chromatograph under the following chromatographic conditions: a chromatographic column: agilent EC-C184.6X 150mm 2.7 μm; flow rate: 0.3 mL/min; detection wavelength: 254 nm; sample introduction amount: 20 mu L of the solution; column temperature: 25 ℃; mobile phase: a: 95% acetonitrile; b: 0.1% formic acid solution; the gradient elution procedure was performed as in table 5 and the chromatogram recorded.
Table 5 flow phase ratio example
| Time(Min) | A(％) | B(％) |
| 0.00 | 20 | 80 |
| 18.00 | 20 | 80 |
| 20.00 | 90 | 10 |
| 40.00 | 90 | 10 |
| 42.00 | 20 | 80 |
Example 6:
the difference between the method for detecting the ibuprofen impurity I and the method for detecting the ibuprofen impurity I in the embodiment 4 is that the ibuprofen impurity I in the embodiment 2 is used for preparing a reference substance solution.
Example 7:
the difference between the method for detecting the ibuprofen impurity I and the method for detecting the ibuprofen impurity I in the embodiment 4 is that the ibuprofen impurity I in the embodiment 3 is used for preparing a reference substance solution.
Example 8:
the difference between the method for detecting the ibuprofen impurity I and the method for detecting the ibuprofen impurity I in the embodiment 4 is that the ibuprofen impurity I in the embodiment 4 is used for preparing a reference substance solution.
Test example 1:
chromatographic system methodology validation of detection methods
1. Detection limit and quantification limit
Taking an ibuprofen test solution and an ibuprofen impurity I reference solution, respectively diluting the ibuprofen test solution and the ibuprofen impurity I reference solution into a series of solubilities, injecting samples under the chromatographic condition of the sample detection of the above example 4' (3), recording a chromatogram, calculating the detection limit of each impurity by using the height of a main component peak which is about 3 times of the baseline noise, and calculating the quantitative limit of each impurity by using the height of the main component peak which is about 10 times of the baseline noise, as shown in Table 6.
2. Linear relation
A series of linear solutions with different mass concentrations are prepared from ibuprofen impurity I reference substance solutions, sample introduction is respectively carried out under the chromatographic conditions of sample detection in the above example 4' (3), and chromatograms are recorded. The linear regression analysis was performed with the injection mass concentration (g/L) as abscissa and the peak area as ordinate, and the ibuprofen impurity I in examples 5, 6, 7 and 8 had good linear correlation within a certain mass concentration range, and the linear range is shown in table 6.
TABLE 6 detection limits, quantitation limits, linear ranges, regression equations, and correlation coefficients for the detection methods
| Group of | Detection limit (mg/L) | Limit of quantitation (mg/L) | Linear Range (mg/L) | Regression equation | R2 |
| Example 5 | 64.33 | 112.67 | 0.446-1.705 | y＝2.85×104x-3.14×103 | 64.33 |
| Example 6 | 66.07 | 114.94 | 0.472-1.689 | y＝2.83×104x-3.16×103 | 66.07 |
| Example 7 | 63.03 | 110.04 | 0.429-1.713 | y＝2.87×104x-3.10×103 | 63.03 |
| Example 8 | 62.96 | 110.01 | 0.430-1.715 | y＝2.87×104x-3.09×103 | 62.96 |
3. Repeatability of
The RSD values were calculated by taking the system suitability solution and sampling 6 times under the chromatographic conditions of example 4 "(3) sample detection" and recording the peak areas, and the RSD% of ibuprofen impurity I in example 5, example 6, example 7 and example 8 were 0.32%, 0.35%, 0.31% and 0.31%, respectively (n ═ 6). The results show that: the methods of example 5, example 6, example 7 and example 8 are good in precision (RSD%. ltoreq.5.0%).
4. Stability test of solution
Taking a reference substance solution and a test substance solution, standing at room temperature, taking the reference substance solution and the test substance solution at 0, 2, 4, 6, 8, 10, 12h and 16h respectively, and injecting samples respectively under the chromatographic condition of sample detection in example 4 (3), wherein RSD% of the peak area of ibuprofen impurity I in example 5, example 6, example 7 and example 8 is respectively as follows: 0.52%, 0.55%, 0.48%, 0.49%. The results show that: the reference solution and the test solution are stable within 16h of preparation.
5. Accuracy test
Test solutions with sample concentrations of 80%, 100% and 120% limit concentration were prepared by sample recovery test, and 9 samples were prepared on average at each level. Samples were each injected under the chromatographic conditions of example 4 "(3) sample detection" and chromatograms were recorded. The average recovery rates of ibuprofen impurity I were 99.97%, 99.91%, 99.98% as measured in example 5, example 6, example 7 and example 8, respectively. The results show that: the average recovery rate of the ibuprofen impurity I is at least 99.90 percent, and the RSD percent is less than or equal to 5.0 percent, which shows that the method has good accuracy.
Conventional techniques in the above embodiments are known to those skilled in the art, and therefore, will not be described in detail herein.
The above embodiments are merely illustrative, and not restrictive, and those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, all equivalent technical solutions also belong to the scope of the present invention, and the protection scope of the present invention should be defined by the claims.
Claims (10)
1. An environment-friendly preparation method of ibuprofen impurity I comprises the following steps:
adding NH to EtOH solution containing ibuprofen impurities H and Zn4And (3) reacting Cl and HCl for 10-15h at 50-90 ℃ under stirring, filtering, evaporating the solvent, and performing column chromatography separation and purification to obtain ibuprofen impurity I.
2. The environmentally friendly process of claim 1, wherein the process comprises the steps of: the ibuprofen impurities H, Zn and NH4The molar ratio of Cl is 1:2: 2.5-3.5.
3. The environmentally friendly process of claim 1, wherein the process comprises the steps of: the dosage ratio of ibuprofen impurity H to HCl is 1:1.5-2.0 (g/mL).
4. The environmentally friendly process of claim 1, wherein the process comprises the steps of: the eluent for column chromatography separation and purification is PE, EA is 10-30: 1.
5. The environmentally friendly process of claim 1, wherein the process comprises the steps of: the yield of the profen impurity I is at least 85.00%.
6. The environmentally friendly process of claim 1, wherein the process comprises the steps of: the lofen impurity H was prepared by the following method:
step 1: a compound shown as a formula (I) and a compound shown as a formula (II) are mixed in NaOC2H5Under the catalytic action of the compound (III), the compound shown in the formula (III) is prepared;
step 2: the compound of formula (III) is in CH3And reacting in the presence of MgBr to obtain ibuprofen impurity H.
7. Ibuprofen impurity I, obtainable by the environmentally friendly preparation method as claimed in any of claims 1-6.
8. An ibuprofen impurity I according to claim 7, characterized in that: the purity of the profen impurity I is at least 99.00%.
9. A method for detecting ibuprofen impurity I, wherein the used standard substance is the ibuprofen impurity I in claim 7 or 8.
10. The method for detecting ibuprofen impurity I according to claim 9, characterized in that: the detection method has good accuracy, the average recovery rate of the ibuprofen impurity I is at least 99.90%, and the RSD is less than or equal to 5%.
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101090891A (en) * | 2004-11-05 | 2007-12-19 | 伦斯勒工业学院 | Methods for treating diseases with 4-hydroxybenzomorphans |
| WO2014132270A2 (en) * | 2013-02-27 | 2014-09-04 | Msn Laboratories Limited | Process for the preparation of 2-(2-aminothiazol-4-yl)-n-[4-(2-{[(2r)-2-hydroxy-2-phenyl ethyl]amino}ethyl)phenyl]acetamide monohydrochloride, its intermediates and polymorph thereof |
| CN105198742A (en) * | 2014-06-30 | 2015-12-30 | 山东诚创医药技术开发有限公司 | Preparation method for 2-aryl-2-glycollic acid esters |
| CN106414377A (en) * | 2014-03-24 | 2017-02-15 | 加利福尼亚大学董事会 | Methods for producing cyclic and acyclic ketones |
| CN106645542A (en) * | 2016-12-20 | 2017-05-10 | 南京艾德凯腾生物医药有限责任公司 | Method for determining dexibuprofen related matter |
| CN106940355A (en) * | 2017-04-24 | 2017-07-11 | 中国药科大学 | A kind of detection method of brufen, its sodium salt and its preparation about material |
| CN107163246A (en) * | 2017-05-20 | 2017-09-15 | 复旦大学 | Reversible thermal contraction polyarylamide of backbone chain type octatomic ring containing dibenzo structure and preparation method thereof |
| CN108181407A (en) * | 2018-02-10 | 2018-06-19 | 扬子江药业集团南京海陵药业有限公司 | A kind of detection method of brufen raw material impurity F |
-
2020
- 2020-02-29 CN CN202010132728.5A patent/CN111205151B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101090891A (en) * | 2004-11-05 | 2007-12-19 | 伦斯勒工业学院 | Methods for treating diseases with 4-hydroxybenzomorphans |
| WO2014132270A2 (en) * | 2013-02-27 | 2014-09-04 | Msn Laboratories Limited | Process for the preparation of 2-(2-aminothiazol-4-yl)-n-[4-(2-{[(2r)-2-hydroxy-2-phenyl ethyl]amino}ethyl)phenyl]acetamide monohydrochloride, its intermediates and polymorph thereof |
| CN106414377A (en) * | 2014-03-24 | 2017-02-15 | 加利福尼亚大学董事会 | Methods for producing cyclic and acyclic ketones |
| CN105198742A (en) * | 2014-06-30 | 2015-12-30 | 山东诚创医药技术开发有限公司 | Preparation method for 2-aryl-2-glycollic acid esters |
| CN106645542A (en) * | 2016-12-20 | 2017-05-10 | 南京艾德凯腾生物医药有限责任公司 | Method for determining dexibuprofen related matter |
| CN106940355A (en) * | 2017-04-24 | 2017-07-11 | 中国药科大学 | A kind of detection method of brufen, its sodium salt and its preparation about material |
| CN107163246A (en) * | 2017-05-20 | 2017-09-15 | 复旦大学 | Reversible thermal contraction polyarylamide of backbone chain type octatomic ring containing dibenzo structure and preparation method thereof |
| CN108181407A (en) * | 2018-02-10 | 2018-06-19 | 扬子江药业集团南京海陵药业有限公司 | A kind of detection method of brufen raw material impurity F |
Non-Patent Citations (4)
| Title |
|---|
| LARA ACEMOGLU等: "Palladium-catalysed enantioselective synthesis of Ibuprofen", 《JOURNAL OF MOLECULAR CATALYSIS A: CHEMICAL》 * |
| M. T. TALIPOV ET AL.: "Dihedral-Angle-Controlled Crossover from Static Hole Delocalization to Dynamic Hopping in Biaryl Cation Radicals", 《ANGEWANDTE CHEMIE》 * |
| TORKIL HOLM: "Mechanism of the Grignard addition reaction.XVI.Homolytic and Concerted Mechanisms in the Reaction of α,β-Unsaturated Carbonyl Compounds with Grinard Reagents", 《ACTA CHEMICA SCANDINAVICA》 * |
| ZUNSHENG HAN ET AL.: "Development and Validation of an HPLC Method for Simultaneous Determination of Ibuprofen and 17 Related compounds", 《CHROMATOGRAPHIA》 * |
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Effective date of registration: 20240123 Address after: Building B402-F20, No.3 Tian'an Digital Innovation Park, No. 449 Huangge North Road, Huanggekeng Community, Longcheng Street, Longgang District, Shenzhen City, Guangdong Province, 518000 Patentee after: Shenzhen Xianggen biomedical Co.,Ltd. Country or region after: China Address before: 518172 room 412, No.1 Park, Shenzhen Overseas Students (Longgang) Pioneer Park, Qinglin West Road, central city, Longcheng street, Longgang District, Shenzhen City, Guangdong Province Patentee before: SHENZHEN SUNGENING BIOTECHNOLOGY CO.,LTD. Country or region before: China |
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