CN108456140B - Method for preparing flurbiprofen impurity M - Google Patents
Method for preparing flurbiprofen impurity M Download PDFInfo
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- CN108456140B CN108456140B CN201810183301.0A CN201810183301A CN108456140B CN 108456140 B CN108456140 B CN 108456140B CN 201810183301 A CN201810183301 A CN 201810183301A CN 108456140 B CN108456140 B CN 108456140B
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- diethyl
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- flurbiprofen
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- 239000012535 impurity Substances 0.000 title claims abstract description 48
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 229960002390 flurbiprofen Drugs 0.000 title claims abstract description 45
- 238000000034 method Methods 0.000 title claims abstract description 37
- 238000006467 substitution reaction Methods 0.000 claims abstract description 20
- UPQZOUHVTJNGFK-UHFFFAOYSA-N diethyl 2-methylpropanedioate Chemical compound CCOC(=O)C(C)C(=O)OCC UPQZOUHVTJNGFK-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000005859 coupling reaction Methods 0.000 claims abstract description 10
- RUBQQRMAWLSCCJ-UHFFFAOYSA-N 1,2-difluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C(F)=C1 RUBQQRMAWLSCCJ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000006193 diazotization reaction Methods 0.000 claims abstract description 7
- 238000006722 reduction reaction Methods 0.000 claims abstract description 7
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 6
- 230000007062 hydrolysis Effects 0.000 claims abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 6
- 239000007858 starting material Substances 0.000 claims abstract description 4
- -1 2-fluoro-4-nitrophenyl Chemical group 0.000 claims description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 26
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 22
- 239000012074 organic phase Substances 0.000 claims description 20
- 238000001035 drying Methods 0.000 claims description 15
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 12
- 235000019260 propionic acid Nutrition 0.000 claims description 11
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 10
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- 235000011181 potassium carbonates Nutrition 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 6
- CGKKDGMMKSOGLM-UHFFFAOYSA-N 1-chloroethyl acetate Chemical compound CC(Cl)OC(C)=O CGKKDGMMKSOGLM-UHFFFAOYSA-N 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 235000010288 sodium nitrite Nutrition 0.000 claims description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- 230000000911 decarboxylating effect Effects 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- PAGZTSLSNQZYEV-UHFFFAOYSA-L 2,2-dimethylpropanoate;palladium(2+) Chemical compound [Pd+2].CC(C)(C)C([O-])=O.CC(C)(C)C([O-])=O PAGZTSLSNQZYEV-UHFFFAOYSA-L 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 230000008878 coupling Effects 0.000 claims description 3
- 238000010168 coupling process Methods 0.000 claims description 3
- PYVFGADNEKZFDO-UHFFFAOYSA-N diethyl 2-(2-fluoro-4-nitrophenyl)-2-methylpropanedioate Chemical compound CCOC(=O)C(C)(C(=O)OCC)C1=CC=C([N+]([O-])=O)C=C1F PYVFGADNEKZFDO-UHFFFAOYSA-N 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 claims description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 3
- MXQOYLRVSVOCQT-UHFFFAOYSA-N palladium;tritert-butylphosphane Chemical compound [Pd].CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C MXQOYLRVSVOCQT-UHFFFAOYSA-N 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 239000012065 filter cake Substances 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 2
- 238000000746 purification Methods 0.000 claims 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- 239000013558 reference substance Substances 0.000 abstract description 5
- 238000010812 external standard method Methods 0.000 abstract description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229960001138 acetylsalicylic acid Drugs 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000010587 phase diagram Methods 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 206010058202 Cystoid macular oedema Diseases 0.000 description 1
- 206010015943 Eye inflammation Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 206010024453 Ligament sprain Diseases 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 208000010040 Sprains and Strains Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000001741 anti-phlogistic effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 210000000695 crystalline len Anatomy 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 229930015704 phenylpropanoid Natural products 0.000 description 1
- 150000002995 phenylpropanoid derivatives Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 210000001747 pupil Anatomy 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- Chemical & Material Sciences (AREA)
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Abstract
The invention discloses a method for preparing flurbiprofen impurity M, which comprises the steps of taking 3, 4-difluoronitrobenzene as a starting material, carrying out substitution reaction with diethyl methylmalonate, and then carrying out reduction reaction, diazotization reaction, coupling reaction, hydrolysis decarboxylation reaction and substitution reaction to obtain high-purity flurbiprofen impurity M. The method for preparing the flurbiprofen impurity M can quickly, simply and efficiently obtain the impurity reference substance, and contributes to the aspects of strictly controlling the quality of flurbiprofen by adopting an external standard method (namely the impurity reference substance method).
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a method for preparing flurbiprofen impurity M.
Background
Flurbiprofen, chemical name 2- (2-fluoro-4-biphenyl) propionic acid, CAS: 5104-49-4, having a chemical structure represented by the formula:
flurbiprofen (Flurbiprofen) is a nonsteroidal anti-inflammatory analgesic developed by the british company, bucz. The medicine is marketed in the United kingdom in 1976, is listed in the pharmacopoeias of the United kingdom, the United states and the like at present, is a powerful phenylpropanoid antipyretic, anti-inflammatory and analgesic drug, is one of excellent nonsteroidal antiphlogistic and analgesic drugs, and can inhibit cyclooxygenase prepared from prostaglandin to play roles in relieving pain, resisting inflammation and relieving fever. The anti-inflammatory and analgesic effects of the aspirin are 250 times and 50 times of that of aspirin (also called acetylsalicylic acid) respectively. Is mainly used for treating rheumatic arthritis, rheumatoid arthritis, ankylosing spondylitis and degenerative arthritis. Can also prevent aphakic cystoid macular edema after the removal of crystalline lens, inhibit pupil contraction during operation, and treat cataract and trabecular formation of eye inflammation after argon laser operation. It is also suitable for pain caused by trauma, sprain, operation, etc.
The quality standards for flurbiprofen are documented in the british pharmacopoeia, the european pharmacopoeia and the us pharmacopoeia, which clearly indicate B, C, D, E, F, G, H, I, J, K, L, M which may be contained, the 12 impurity having the following structure:
the 12 impurities are subjected to a systematic adaptability test in a mixing and contrasting mode to control the impurities, and no efficient synthesis method for preparing the flurbiprofen impurity M is found in the existing literature.
The technical guidelines for chemical drug impurity research (GPH 3-1, pages 6-7) point out: the detection of organic impurities is generally carried out by HPLC. If the HPLC method is adopted, a peak area method is required, and an external standard method (impurity reference substance method) is adopted as a specific quantitative method, so that the external standard method is relatively accurate in quantification.
The flurbiprofen impurity M is one of the impurities of interest in the quality standard of flurbiprofen, and is of great significance for the relevant studies on the flurbiprofen impurity. Therefore, the method for simply, conveniently and efficiently preparing the high-purity flurbiprofen impurity M is provided, and has great significance for relevant research on the flurbiprofen impurity. The method can be used for qualitative and quantitative analysis of impurities in flurbiprofen production, so that the quality standard of flurbiprofen can be improved, and important guiding significance is provided for safe medication of the masses.
Disclosure of Invention
The present invention aims to provide a method for preparing flurbiprofen impurity M, so as to solve the problems in the background art.
In order to achieve the purpose, the invention provides the following technical scheme:
a method for preparing flurbiprofen impurity M comprises the steps of taking 3, 4-difluoronitrobenzene as a starting material, carrying out substitution reaction with diethyl methylmalonate, and then carrying out reduction reaction, diazotization reaction, coupling reaction, hydrolysis decarboxylation reaction and substitution reaction to obtain high-purity flurbiprofen impurity M; the overall reaction flow is:
as a further scheme of the invention: the flurbiprofen impurity M is obtained by substitution reaction of 1-chloroethyl acetate and 2- (2-fluoro-4-phenyl) propionic acid under alkaline conditions, and the reaction equation is as follows:
as a further scheme of the invention: the alkali is potassium carbonate, sodium carbonate, potassium tert-butoxide or triethylamine.
As a further scheme of the invention: the 2- (2-fluoro-4-phenyl) propionic acid is obtained by hydrolyzing and decarboxylating (3-fluoro [1,1' -biphenyl ] -4-yl) methyl diethyl malonate under alkaline conditions, and the reaction equation is as follows:
as a further scheme of the invention: the (3-fluoro [1,1' -biphenyl ] -4-yl) methyl diethyl malonate is prepared by coupling 2- (2-fluoro-4-iodophenyl) -2-methyl diethyl malonate and phenylboronic acid under an alkaline condition by adding a catalyst, and the reaction equation is as follows:
as a further scheme of the invention: the catalyst is tetrakis (triphenylphosphine) palladium, bis (tri-tert-butylphosphine) palladium, triphenylphosphine, palladium acetate, palladium pivalate or palladium trifluoroacetate.
As a further scheme of the invention: the 2- (2-fluoro-4-iodophenyl) -2-methyl diethyl malonate is obtained by diazotizing 2- (2-fluoro-4-aminophenyl) -2-methyl diethyl malonate with sodium nitrite and potassium iodide under an acidic condition, and the reaction equation is as follows:
as a further scheme of the invention: the diethyl 2- (2-fluoro-4-aminophenyl) -2-methyl malonate is obtained by reducing diethyl 2- (2-fluoro-4-nitrophenyl) -2-methyl malonate, and the reaction equation is as follows:
as a further scheme of the invention: the 2- (2-fluoro-4-nitrophenyl) -2-diethyl methylmalonate is obtained by substitution reaction of 3, 4-difluoronitrobenzene and diethyl methylmalonate under an alkaline condition, and the reaction equation is as follows:
as a further scheme of the invention: the alkali is potassium tert-butoxide, sodium methoxide or sodium hydride.
Compared with the prior art, the invention has the beneficial effects that:
the method for preparing the flurbiprofen impurity M can quickly, simply and efficiently obtain the impurity reference substance, and contributes to the aspects of strictly controlling the quality of flurbiprofen by adopting an external standard method (namely the impurity reference substance method).
Drawings
Fig. 1 is a gas phase diagram of flurbiprofen impurity M of the present invention.
Fig. 2 is a mass spectrum of flurbiprofen impurity M of the present invention.
FIG. 3 is a nuclear magnetic diagram of flurbiprofen impurity M of the present invention (the solvent is CDCl)3)。
Detailed Description
The technical solution of the present patent will be described in further detail with reference to the following embodiments.
A method for preparing flurbiprofen impurity M comprises the steps of taking 3, 4-difluoronitrobenzene as a starting material, carrying out substitution reaction with diethyl methylmalonate, and then carrying out reduction reaction, diazotization reaction, coupling reaction, hydrolysis decarboxylation reaction and substitution reaction to obtain high-purity flurbiprofen impurity M; the overall reaction flow is:
the method for preparing the flurbiprofen impurity M comprises the following specific steps:
the first step is as follows: and (3) performing substitution reaction to synthesize a compound 5, namely 2- (2-fluoro-4-nitrophenyl) -2-diethyl methylmalonate. The 2- (2-fluoro-4-nitrophenyl) -2-diethyl methylmalonate is obtained by the substitution reaction of 3, 4-difluoronitrobenzene and diethyl methylmalonate under the alkaline condition. The method comprises the following steps: adding 12.04g diethyl methylmalonate and 100ml anhydrous THF into a 250m single-neck bottle, stirring, adding 8.91g potassium tert-butoxide (sodium tert-butoxide, sodium methoxide or sodium hydride can be replaced by) at 0-5 ℃, stirring for 30 minutes, slowly adding 3, 4-difluoronitrobenzene, reacting for 12 hours at 20-25 ℃, concentrating and drying after the reaction is finished, adding 100ml saturated ammonium chloride solution, extracting with 150ml ethyl acetate, washing an organic phase with 100ml saturated sodium chloride solution, concentrating and drying to obtain 18.1g yellow oily 2- (2-fluoro-4-nitrophenyl) -2-diethyl methylmalonate, wherein the yield is 92%.
The second step is that: and (3) carrying out reduction reaction to synthesize a compound 4, namely 2- (2-fluoro-4-aminophenyl) -2-methyl diethyl malonate. 2- (2-fluoro-4-aminophenyl) -2-methyl diethyl malonate was reduced from 2- (2-fluoro-4-nitrophenyl) -2-methyl diethyl malonate. The method comprises the following steps: adding 7.0g of diethyl 2- (2-fluoro-4-nitrophenyl) -2-methyl malonate and 45ml of ethanol (the solvent can be replaced by methanol, benzene, toluene, acetonitrile or 1, 2-dichloroethane) into a 100ml single-neck bottle, stirring, adding 700mg of palladium carbon (the reducing agent can be replaced by iron powder, zinc powder, sodium hydrosulfide, sodium thiosulfate or hydrazine hydrate) at 15-20 ℃, introducing hydrogen at 20-25 ℃ for reaction for 14h, filtering after the reaction is finished, washing a filter cake with 30ml of ethyl acetate, concentrating and drying the filtrate to obtain 5.7g of yellow oily diethyl 2- (2-fluoro-4-aminophenyl) -2-methyl malonate with the yield of 90%.
The third step: diazotizing, and synthesizing a compound 3, namely 2- (2-fluoro-4-iodophenyl) -2-methyl diethyl malonate. The 2- (2-fluoro-4-iodophenyl) -2-methyl diethyl malonate is obtained by diazotization reaction of 2- (2-fluoro-4-aminophenyl) -2-methyl diethyl malonate with sodium nitrite and potassium iodide under acidic conditions. The method comprises the following steps: 6.428g of diethyl 2- (2-fluoro-4-aminophenyl) -2-methylmalonate, 43ml of water and 40ml of toluene are added into a 250ml single-neck bottle, the mixture is stirred, 9ml of concentrated hydrochloric acid is added dropwise at the temperature of 0-5 ℃, the mixture is stirred for 30min, 1.9g of sodium nitrite aqueous solution is added dropwise again, the mixture is reacted for 30min, 7.62g of potassium iodide is added, the mixture is reacted for 4h at the temperature of 20-25 ℃, 40ml of water and 60ml of ethyl acetate are added for extraction after the reaction is finished, an organic phase is washed by 30ml of saturated sodium chloride solution, an anhydrous sodium sulfate is used for drying the organic phase, and 6.8g of brownish red oily diethyl 2- (2-fluoro-4-iodophenyl) -2-methylmalonate is obtained after the organic phase is concentrated and.
The fourth step: coupling reaction to synthesize compound 2, namely (3-fluoro [1,1' -biphenyl ] -4-yl) methyl diethyl malonate. Diethyl (3-fluoro [1,1' -biphenyl ] -4-yl) methylmalonate is obtained by coupling diethyl 2- (2-fluoro-4-iodophenyl) -2-methylmalonate and phenylboronic acid under alkaline conditions with the addition of a catalyst. The method comprises the following steps: 6.4g of 2- (2-fluoro-4-iodophenyl) -2-methyl diethyl malonate, 46ml of tetrahydrofuran and 40ml of water are added into a 250ml single-neck bottle and stirred, 6.8g of potassium carbonate (sodium carbonate, sodium bicarbonate, potassium bicarbonate or the like can be replaced by) and 2.2g of phenylboronic acid and 640mg of tetrakis (triphenylphosphine) palladium (a catalyst can be replaced by bis (tri-tert-butylphosphine) palladium, triphenylphosphine, palladium acetate, palladium pivalate or palladium trifluoroacetate and the like) are added into the single-neck bottle at the temperature of 20-25 ℃ for reflux reaction for 14 hours. After the reaction, the reaction mixture was filtered, the filtrate was extracted with ethyl acetate, the organic phase was washed with a saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give 5.1g of pale yellow oily (3-fluoro [1,1' -biphenyl ] -4-yl) diethyl methylmalonate with a yield of 90.5%.
The fifth step: hydrolyzing and decarboxylating to synthesize the compound 1, namely 2- (2-fluoro-4-phenyl) propionic acid. 2- (2-fluoro-4-phenyl) propionic acid is obtained by hydrolysis decarboxylation of (3-fluoro [1,1' -biphenyl ] -4-yl) methyl diethyl malonate under alkaline conditions. The method comprises the following steps: a100 ml single-neck flask was charged with 4.5g of (3-fluoro [1,1' -biphenyl ] -4-yl) methyl diethyl malonate, 25ml of ethanol and 25ml of water, stirred, added with 2.6g of sodium hydroxide (lithium hydroxide or potassium hydroxide may be used instead), and refluxed at 80 ℃ for 10 hours. Concentrating and drying ethanol, adding 50ml of water, adjusting the pH value to 1-3 by using dilute hydrochloric acid, extracting and layering ethyl acetate, washing an organic phase by using 40ml of saturated sodium chloride solution, drying the organic phase by using anhydrous sodium sulfate, concentrating, drying and purifying to obtain 2.7g of white to off-white solid powder 2- (2-fluoro-4-phenyl) propionic acid, wherein the yield is 85%.
And a sixth step: and (4) carrying out substitution reaction to synthesize flurbiprofen impurity M. The flurbiprofen impurity M is obtained by the substitution reaction of 1-chloroethyl acetate and 2- (2-fluoro-4-phenyl) propionic acid under the alkaline condition. The method comprises the following steps: adding 0.6g of reaction substrate and 10ml of dichloromethane into a 50ml single-neck bottle, stirring and cooling, adding 750mg of potassium carbonate (sodium carbonate, potassium tert-butoxide or triethylamine can be replaced by the above materials) at room temperature, reacting for 10min, slowly dropwise adding 451mg of 1-chloroethyl acetate, and dropwise adding for 10 min. After 10min, the mixture is heated to 30-45 ℃ for reaction for 14h, concentrated and dried after the reaction is finished, saturated ammonium chloride is added at 0 ℃ to adjust the pH value to 7, 20ml of ethyl acetate is used for extraction, an organic phase is separated, the organic phase is washed by 10ml of saturated sodium chloride solution, concentrated and dried to obtain 690mg of colorless to pale yellow oily flurbiprofen impurity M, the yield is 85%, and GC is more than or equal to 98.0%.
Fig. 1-2 is a gas phase diagram and a mass spectrogram of flurbiprofen impurity M of the present invention, and the detection parameters are as follows:
sample introduction name: FBLFM121901-1
Sample introduction volume: 1.00
The method comprises the following steps: e: \\ GCMS-DATA \2017\10\30\ SH-Rxi-5Sil MS-40-140-310.qgm
Data file: e: \\ GCMS-DATA \2017\12\ FBLFM121901-1.qgd
The detection result is as follows:
peak Table TIC
Library of spectra
Target Components
Line number #: 1 retention time: 17.720 (scan # 3025) mass peak: 420
Original mode: single 17.720(3025) base peak: 199.05(7937500)
Background mode: group-free 1-event 1 Scan
Although the preferred embodiments of the present patent have been described in detail, the present patent is not limited to the above embodiments, and various changes can be made without departing from the spirit of the present patent within the knowledge of those skilled in the art.
Claims (6)
1. The method for preparing the flurbiprofen impurity M is characterized in that 3, 4-difluoronitrobenzene is used as a starting material and is subjected to substitution reaction with diethyl methylmalonate, and then the high-purity flurbiprofen impurity M is obtained through reduction reaction, diazotization reaction, coupling reaction, hydrolysis decarboxylation reaction and substitution reaction; the overall reaction flow is:
the method comprises the following specific steps:
the first step is as follows: substitution reaction to synthesize 2- (2-fluoro-4-nitrophenyl) -2-diethyl methylmalonate; 2- (2-fluoro-4-nitrophenyl) -2-diethyl methylmalonate is obtained by substitution reaction of 3, 4-difluoronitrobenzene and diethyl methylmalonate under alkaline condition; the method comprises the following steps: adding 12.04g diethyl methylmalonate and 100ml anhydrous THF into a bottle, stirring, adding 8.91g potassium tert-butoxide at 0-5 ℃, stirring for 30 minutes after the addition is finished, then slowly adding 3, 4-difluoronitrobenzene, reacting for 12 hours at 20-25 ℃, concentrating and drying after the reaction is finished, adding 100ml saturated ammonium chloride solution, extracting with 150ml ethyl acetate, washing an organic phase with 100ml saturated sodium chloride solution, and concentrating and drying to obtain yellow oily 2- (2-fluoro-4-nitrophenyl) -2-diethyl methylmalonate;
the second step is that: reduction reaction to synthesize 2- (2-fluoro-4-aminophenyl) -2-methyl diethyl malonate; the 2- (2-fluoro-4-aminophenyl) -2-methyl diethyl malonate is obtained by reducing 2- (2-fluoro-4-nitrophenyl) -2-methyl diethyl malonate; the method comprises the following steps: adding 7.0g of diethyl 2- (2-fluoro-4-nitrophenyl) -2-methyl malonate and 45ml of ethanol into a bottle, stirring, adding 700mg of palladium carbon at 15-20 ℃, introducing hydrogen at 20-25 ℃ for reacting for 14h, filtering after the reaction is finished, washing a filter cake with 30ml of ethyl acetate, and concentrating and drying the filtrate to obtain yellow oily diethyl 2- (2-fluoro-4-aminophenyl) -2-methyl malonate;
the third step: diazotization reaction to synthesize 2- (2-fluoro-4-iodophenyl) -2-methyl diethyl malonate; 2- (2-fluoro-4-iodophenyl) -2-methyl diethyl malonate is obtained by diazotization reaction of 2- (2-fluoro-4-aminophenyl) -2-methyl diethyl malonate with sodium nitrite and potassium iodide under acidic conditions; the method comprises the following steps: adding 6.428g of diethyl 2- (2-fluoro-4-aminophenyl) -2-methyl malonate, 43ml of water and 40ml of toluene into a bottle, stirring, dropwise adding 9ml of concentrated hydrochloric acid at 0-5 ℃, stirring for 30min, dropwise adding 1.9g of sodium nitrite aqueous solution, reacting for 30min, adding 7.62g of potassium iodide, reacting for 4h at 20-25 ℃, adding 40ml of water and 60ml of ethyl acetate for extraction after the reaction is finished, washing an organic phase with 30ml of saturated sodium chloride solution, drying the organic phase with anhydrous sodium sulfate, and concentrating and drying the organic phase to obtain brownish red oily diethyl 2- (2-fluoro-4-iodophenyl) -2-methyl malonate;
the fourth step: coupling reaction to synthesize (3-fluoro [1,1' -biphenyl ] -4-yl) methyl diethyl malonate; diethyl (3-fluoro [1,1' -biphenyl ] -4-yl) methylmalonate is prepared by coupling diethyl 2- (2-fluoro-4-iodophenyl) -2-methylmalonate and phenylboronic acid under an alkaline condition by adding a catalyst; the method comprises the following steps: adding 6.4g of diethyl 2- (2-fluoro-4-iodophenyl) -2-methylmalonate, 46ml of tetrahydrofuran and 40ml of water into a bottle, stirring, adding 6.8g of potassium carbonate, 2.2g of phenylboronic acid and 640mg of tetrakis (triphenylphosphine) palladium at 20-25 ℃, and carrying out reflux reaction for 14 h; filtering after the reaction is finished, extracting filtrate by ethyl acetate, washing an organic phase by saturated sodium chloride solution, drying the organic phase by anhydrous sodium sulfate, and concentrating and drying to obtain light yellow oily (3-fluoro [1,1' -biphenyl ] -4-yl) diethyl methylmalonate;
the fifth step: hydrolyzing and decarboxylating to synthesize 2- (2-fluoro-4-phenyl) propionic acid; 2- (2-fluoro-4-phenyl) propionic acid is obtained by hydrolyzing and decarboxylating (3-fluoro [1,1' -biphenyl ] -4-yl) methyl diethyl malonate under alkaline conditions; the method comprises the following steps: adding 4.5g (3-fluoro [1,1' -biphenyl ] -4-yl) methyl diethyl malonate, 25ml ethanol and 25ml water into a bottle, stirring, adding 2.6g sodium hydroxide, and refluxing at 80 ℃ for 10 hours; adding 50ml of water into concentrated dry ethanol, adjusting the pH value to be 1-3 by using dilute hydrochloric acid, extracting and layering ethyl acetate, washing an organic phase by using 40ml of saturated sodium chloride solution, drying the organic phase by using anhydrous sodium sulfate, and carrying out concentrated dry purification to obtain white to off-white solid powder 2- (2-fluoro-4-phenyl) propionic acid;
and a sixth step: substitution reaction, synthesizing flurbiprofen impurity M; the flurbiprofen impurity M is obtained by the substitution reaction of 1-chloroethyl acetate and 2- (2-fluoro-4-phenyl) propionic acid under the alkaline condition; the method comprises the following steps: adding 0.6g of reaction substrate and 10ml of dichloromethane into a bottle, stirring and cooling, adding 750mg of potassium carbonate at room temperature, reacting for 10min, slowly dropwise adding 451mg of 1-chloroethyl acetate for 10 min; after 10min, the temperature is raised to 30-45 ℃ for reaction for 14h, the reaction is concentrated and dried, saturated ammonium chloride is added at 0 ℃ to adjust the pH value to 7, 20ml of ethyl acetate is used for extraction, an organic phase is separated, the organic phase is washed by 10ml of saturated sodium chloride solution, and the mixture is concentrated and dried to obtain the flurbiprofen impurity M which is colorless to light yellow oily.
2. The method for preparing flurbiprofen impurity M according to claim 1, wherein in the first substitution reaction, potassium tert-butoxide is replaced by sodium tert-butoxide.
3. The method for preparing flurbiprofen impurity M according to claim 1, wherein in the second reduction step, ethanol is replaced with methanol.
4. The method for preparing flurbiprofen impurity M according to claim 1, wherein in the fourth coupling reaction step, potassium carbonate is replaced by sodium carbonate, sodium bicarbonate or potassium bicarbonate; the tetrakis (triphenylphosphine) palladium is replaced by bis (tri-tert-butylphosphine) palladium, palladium acetate, palladium pivalate or palladium trifluoroacetate.
5. The method for preparing flurbiprofen impurity M according to claim 1, wherein in the fifth step of hydrolysis decarboxylation, sodium hydroxide is replaced by lithium hydroxide or potassium hydroxide.
6. The method for preparing flurbiprofen impurity M according to claim 1, wherein in the sixth substitution reaction, potassium carbonate is replaced with sodium carbonate.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4766148A (en) * | 1983-02-19 | 1988-08-23 | Kaken Pharmaceutical Co., Ltd. | Biphenylylpropionic acid derivative and pharmaceutical composition containing the same |
| CN103012111A (en) * | 2012-09-12 | 2013-04-03 | 衢州学院 | Preparation method 2,4,5-trifluorophenylacetic acid |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4766148A (en) * | 1983-02-19 | 1988-08-23 | Kaken Pharmaceutical Co., Ltd. | Biphenylylpropionic acid derivative and pharmaceutical composition containing the same |
| CN103012111A (en) * | 2012-09-12 | 2013-04-03 | 衢州学院 | Preparation method 2,4,5-trifluorophenylacetic acid |
Non-Patent Citations (3)
| Title |
|---|
| "Synthesis and Biological Activity of Flurbiprofen Analogues as Selective Inhibitors of β-Amyloid1-42 Secretion";Ilaria Peretto et al.,;《J. Med. Chem.,》;20050806;第48卷(第18期);第5705-5720页 * |
| "Synthesis and Biological Evaluation of Derivatives of 2-{2-Fluoro-4-[(2-oxocyclopentyl)methyl]phenyl}propanoic Acid: Nonsteroidal Anti-Inflammatory Drugs with Low Gastric Ulcerogenic Activity";Naoki Yamakawa et al.,;《J. Med. Chem.,》;20120312;第55卷;第5143-5150页 * |
| "Targeted Fluorination of a Nonsteroidal Anti‐inflammatory Drug to Prolong Metabolic Half-Life";Maxwell J Shaughnessy et al.,;《chemmedchem》;20140128;第9卷(第4期);第734页Scheme 3 * |
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