CN114181215B - Preparation method of ketorolac or related impurities of ketorolac salt - Google Patents
Preparation method of ketorolac or related impurities of ketorolac salt Download PDFInfo
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- CN114181215B CN114181215B CN202111614113.7A CN202111614113A CN114181215B CN 114181215 B CN114181215 B CN 114181215B CN 202111614113 A CN202111614113 A CN 202111614113A CN 114181215 B CN114181215 B CN 114181215B
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- Prior art keywords
- dihydro
- ketorolac
- benzoyl
- pyrrolizine
- reaction
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- 229960004752 ketorolac Drugs 0.000 title claims abstract description 33
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 239000012535 impurity Substances 0.000 title claims description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- DHUITNLXEMJSMU-UHFFFAOYSA-N 6,7-dihydro-5h-pyrrolizin-3-yl(phenyl)methanone Chemical compound C=1C=C2CCCN2C=1C(=O)C1=CC=CC=C1 DHUITNLXEMJSMU-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000000203 mixture Substances 0.000 claims abstract description 20
- 238000001914 filtration Methods 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 18
- 229910052751 metal Inorganic materials 0.000 claims abstract description 17
- 239000002184 metal Substances 0.000 claims abstract description 17
- 230000001590 oxidative effect Effects 0.000 claims abstract description 15
- 239000007800 oxidant agent Substances 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- NFKBMHXYCKRXPQ-UHFFFAOYSA-N 5-benzoyl-2,3-dihydropyrrolizin-1-one Chemical compound C=1C=C2C(=O)CCN2C=1C(=O)C1=CC=CC=C1 NFKBMHXYCKRXPQ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 239000002798 polar solvent Substances 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 16
- -1 lithium aluminum hydride Chemical compound 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 11
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 8
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 8
- 239000012286 potassium permanganate Substances 0.000 claims description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 claims description 6
- 238000006555 catalytic reaction Methods 0.000 claims description 5
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- 229940117975 chromium trioxide Drugs 0.000 claims description 4
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 4
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 claims description 3
- HKVFISRIUUGTIB-UHFFFAOYSA-O azanium;cerium;nitrate Chemical compound [NH4+].[Ce].[O-][N+]([O-])=O HKVFISRIUUGTIB-UHFFFAOYSA-O 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 238000006722 reduction reaction Methods 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 239000006227 byproduct Substances 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- 238000001816 cooling Methods 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 17
- 238000004809 thin layer chromatography Methods 0.000 description 15
- 239000007787 solid Substances 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000002425 crystallisation Methods 0.000 description 12
- 230000008025 crystallization Effects 0.000 description 12
- 238000012544 monitoring process Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 238000001035 drying Methods 0.000 description 10
- 238000010791 quenching Methods 0.000 description 10
- PPQHNULBCSHICE-UHFFFAOYSA-N (7-hydroxy-6,7-dihydro-5h-pyrrolizin-3-yl)-phenylmethanone Chemical compound OC1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 PPQHNULBCSHICE-UHFFFAOYSA-N 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- BWHLPLXXIDYSNW-UHFFFAOYSA-N ketorolac tromethamine Chemical compound OCC(N)(CO)CO.OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 BWHLPLXXIDYSNW-UHFFFAOYSA-N 0.000 description 9
- 238000000605 extraction Methods 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 229960004384 ketorolac tromethamine Drugs 0.000 description 7
- 230000000171 quenching effect Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 238000012790 confirmation Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 2
- BTVWZWFKMIUSGS-UHFFFAOYSA-N dimethylethyleneglycol Natural products CC(C)(O)CO BTVWZWFKMIUSGS-UHFFFAOYSA-N 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- WFRBDWRZVBPBDO-UHFFFAOYSA-N tert-hexyl alcohol Natural products CCCC(C)(C)O WFRBDWRZVBPBDO-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000003541 multi-stage reaction 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
- 239000003495 polar organic solvent Substances 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Abstract
The invention discloses a preparation method of a related substance of ketorolac or a salt thereof, which comprises the following steps: adding a metal catalyst into an organic solvent by taking ketorolac or ketorolac as an initial raw material, filtering the rest metal catalyst after the reaction is finished, and crystallizing to obtain 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) ketone; dissolving 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) ketone with a solvent, oxidizing the solution by an oxidant, and crystallizing the solution to obtain 5-benzoyl-2, 3-dihydropyrrolizine-1-ketone; adding 5-benzoyl-2, 3-dihydro-pyrrolizine-1-one into a polar solvent, reducing the mixture by using a reducing agent, and crystallizing the mixture to obtain (1 RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-ol. The invention has simple operation, convenient and easily obtained raw materials, and the total yield can reach more than 70 percent. Compared with the preparation method in the prior art, the method has the advantages of few byproducts, remarkably increased yield, simple preparation method and no need of complicated and severe conditions, and can obtain related substances with high purity and high yield.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of related impurities of ketorolac or a salt thereof.
Background
Ketorolac tromethamine is a non-steroidal anti-inflammatory drug which can inhibit prostaglandin biosynthesis, has analgesic effect, and has no sedative or anxiolytic effect, so that the ketorolac tromethamine is widely applied to perioperative analgesia. Quality standards were received for the controller product quality U.S. pharmacopoeia (USP) version 43 and European Pharmacopoeia (EP) version 10.0.
In the research process of product quality research, several related substances including (1 RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizin-1-ol (EP 10.0 version of impurity A), 6, 7-dihydro-5H-pyrrolizin-3-yl (phenyl) methanone (EP 10.0 version of impurity I) and 5-benzoyl-2, 3-dihydropyrrolidin-1-one (EP 10.0 version of impurity B) are recorded in pharmacopoeia of each country, and the related impurities are required to be controlled, so that related impurity reference substances are difficult to obtain, and the research and detection of ketorolac tromethamine related impurities are seriously influenced.
At present, the preparation methods of (1 RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-ol (EP 10.0 edition of impurity A), 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) methanone (EP 10.0 edition of impurity I) and 5-benzoyl-2, 3-dihydro pyrrolizine-1-ketone (EP 10.0 edition of impurity B) are reported in a few places at home and abroad. The foreign part is that potassium permanganate is added into ketorolac tromethamine, and (1 RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-ol (EP 10.0 edition impurity A) is formed under an alkaline solvent, but the recovery rate is not high, in addition, column separation is needed, and the reaction process is complicated. In addition, the foreign countries also have the steps of adding polar solvent and ferric trichloride into ketorolac, reacting in oxygen atmosphere, and obtaining 5-benzoyl-2, 3-dihydropyrrolidin-1-one (EP 10.0 version of impurity B) through multi-step reaction.
Disclosure of Invention
The embodiment of the invention provides a preparation method of ketorolac or related impurities of salts thereof, in particular relates to a preparation method of (1 RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-ol (EP 10.0 version of impurity A), 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) methanone (EP 10.0 version of impurity I) and 5-benzoyl-2, 3-dihydropyrrolizine-1-one (EP 10.0 version of impurity B), and aims to efficiently and simply obtain a high-purity impurity reference substance for researching and detecting ketorolac tromethamine related impurities.
The technical scheme adopted by the invention comprises the following steps:
(1) Adding a metal catalyst into an organic solvent by taking ketorolac or ketorolac as an initial raw material, filtering the residual metal catalyst after the reaction, and crystallizing to obtain 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) methanone;
(2) Dissolving 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) ketone with a solvent, oxidizing the solution by an oxidant, and crystallizing the solution to obtain 5-benzoyl-2, 3-dihydropyrrolizine-1-ketone;
(3) Adding 5-benzoyl-2, 3-dihydro-pyrrolizine-1-one into a polar solvent, reducing the mixture by using a reducing agent, and crystallizing the mixture to obtain (1 RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-ol.
Preferably, the metal catalyst is copper powder or iron powder, more preferably copper powder. Compared with other metal catalysts, the addition of copper powder or iron powder can improve the selectivity, reduce byproducts and greatly improve the yield of the 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) ketone.
Preferably, the temperature in the metal catalysis process is 90-180 ℃, and the reaction time is 4-18 h. Further, the temperature in the metal catalysis process is 120-150 ℃, and the catalysis efficiency of the metal catalyst is higher at the temperature.
Preferably, in the step (2), the reaction time is 0.5 to 6 hours under the condition of 30 to 95 ℃ through oxidation by an oxidant. Further, the oxidation reaction is more complete at the temperature of 70-80 ℃ by oxidizing with an oxidizing agent.
Preferably, in the step (1), the organic solvent is one or a mixture of more than one of toluene, paraxylene, N-methylpyrrolidone, dimethylacetamide, dimethylformamide, dimethyl sulfoxide, ethylene glycol and butanol. Preferably, N-methylpyrrolidone, dimethylacetamide, dimethylformamide, dimethylsulfoxide, ethylene glycol and butanol are used, and the yield can be remarkably improved by using a high-boiling-point strongly polar organic solvent, for example, dimethylformamide, ethylene glycol or the like.
Preferably, in the step (1), the ketorolac salt is one or a mixture of any more of ketorolac tromethamine salt, ketorolac triethylamine salt, ketorolac diisopropylamine salt, ketorolac ammonium salt, ketorolac sodium salt and ketorolac potassium salt.
Preferably, in step (2), the oxidizing agent may be one or a mixture of any of hydrogen peroxide, nitric acid, potassium permanganate, ammonium cerium nitrate, potassium dichromate, chromium trioxide; the molar ratio of the 6, 7-dihydro-5H-pyrrolizin-3-yl (phenyl) to the oxidant is 1:1-1:10.
Preferably, in the step (3), the reducing agent is one or a mixture of any more of lithium aluminum hydride, sodium borohydride and aluminum isopropoxide; the mol ratio of the 5-benzoyl-2, 3-dihydropyrrolidin-1-ketone to the reducing agent is 1:0.8-1:4.0; the reduction reaction time is 1-6 h, and the reaction temperature is-20-80 ℃. Preferably, the equivalent of the reducing agent is selected to be 0.8 to 1.0, and exceeding the equivalent greatly affects the yield.
In some embodiments of the present invention, acetic acid may be added to the reaction system in the step (2), so as to promote the reaction. The amount of acetic acid may be 10 times the mass of the reaction substrate of step (2).
Certain embodiments of the present invention provide a method for preparing a ketorolac or related impurity of a salt thereof, the method comprising the steps of:
(1) Adding a metal catalyst into an organic solvent by taking ketorolac or ketorolac as an initial raw material, and sequentially filtering out the rest metal catalyst after the reaction is finished, extracting, separating and purifying to obtain 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) methanone;
(2) Dissolving 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) ketone with a solvent, oxidizing with an oxidant at 70-80 ℃, quenching, extracting, merging organic phases, concentrating to dryness, crystallizing, filtering and drying to obtain 5-benzoyl-2, 3-pyrrolizine-1-ketone;
(3) Adding a polar solvent into 5-benzoyl-2, 3-dihydro-pyrrolizine-1-one, reducing with a reducing agent, quenching, extracting, merging organic phases, concentrating to dry crystals after the reaction is completed, and obtaining (1 RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-ol.
In the step (1), ketorolac salt may be ketorolac tromethamine salt, ketorolac triethylamine salt, ketorolac diisopropylamine salt, ketorolac ammonium salt, ketorolac sodium salt, or ketorolac potassium salt, or a mixture of any more of them. The metal catalyst is copper powder, iron powder and the like. The organic solvent is one or a mixture of more than one of toluene, paraxylene, pyridine, dimethylformamide, dimethyl sulfoxide, ethylene glycol and butanol. The reaction temperature is 120-150 ℃, the reaction time is 4-18 h, and the concentration crystallization temperature is-10 ℃.
In step (2), the oxidizing agent may be one or a mixture of any of hydrogen peroxide, nitric acid, potassium permanganate, ammonium cerium nitrate, potassium dichromate, and chromium trioxide. The molar ratio of the 6, 7-dihydro-5H-pyrrolizin-3-yl (phenyl) ketone to the oxidant is 1:1-1:10. The solvent is one or a mixture of any more of acetic acid, acetone, tetrahydrofuran and water. The temperature is 30-95 ℃ in the oxidation reaction process, the reaction time is 0.5-6 h, the temperature is reduced to 20-40 ℃ after the reaction is finished, and the crystallization time is 2-3 h. Acetic acid can be added into the reaction system of the step (2), and the mass of the acetic acid can be 10 times that of the 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) ketone.
In the step (3), the reducing agent is one or a mixture of any more of lithium aluminum hydride, sodium borohydride and aluminum isopropoxide. The mol ratio of the 5-benzoyl-2, 3-dihydropyrrolidin-1-one to the reducing agent is 1:0.8-1:4.0. The reduction reaction time is 1-6 h, and the reaction temperature is-20-80 ℃.
The overall reaction equation is as follows:
the beneficial effects of the invention are as follows:
(1) The invention provides a brand-new preparation method of ketorolac or related impurities of the ketorolac salt, which is simple to operate, has convenient and easily obtained raw materials, and has the total yield of more than 70 percent. The purity of the prepared (1 RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-ol reaches more than 98 percent, the purity of the 5-benzoyl-2, 3-dihydro-pyrrolizine-1-ketone reaches more than 99 percent, the purity of the 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) methanone reaches more than 99 percent, the requirements of serving as an impurity reference substance are met, and the method plays a positive role in researching and inspecting related impurities of ketorolac tromethamine.
(2) Compared with the preparation method in the prior art, the method has the advantages of few byproducts, remarkably increased yield, simple preparation method and no need of complicated and severe conditions, and can obtain related substances with high purity and high yield.
Drawings
FIG. 1 shows the mass spectrum of intermediate 6, 7-dihydro-5H-pyrrolizin-3-yl (phenyl) methanone of example 1 of the present invention.
FIG. 2 is a chromatogram of intermediate 6, 7-dihydro-5H-pyrrolizin-3-yl (phenyl) methanone of example 1 of the present invention.
FIG. 3 shows a hydrogen spectrum of intermediate 6, 7-dihydro-5H-pyrrolizin-3-yl (phenyl) methanone of example 1 of the present invention.
FIG. 4 is a mass spectrum of 5-benzoyl-2, 3-dihydropyrrolidin-1-one intermediate of example 1 of the present invention.
FIG. 5 is a chromatogram of intermediate 5-benzoyl-2, 3-dihydropyrrolidin-1-one of example 1 of the present invention.
FIG. 6 is a graph showing the hydrogen profile of 5-benzoyl-2, 3-dihydropyrrolidin-1-one, an intermediate of example 1 of the present invention.
FIG. 7 is a mass spectrum of (1 RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizin-1-ol of example 1 of the present invention.
FIG. 8 is a hydrogen spectrum of (1 RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizin-1-ol of example 1 of the present invention.
FIG. 9 is a graph of the (1 RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizin-1-ol carbon of example 1 of the present invention.
FIG. 10 is a chromatogram of (1 RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizin-1-ol of example 1 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail with reference to the accompanying drawings, but embodiments of the present invention are not limited thereto.
Example 1
Taking 500ml of a single-port bottle, adding 20g of ketorolac, adding 100g of DMF (i.e. dimethylformamide), adding 5g of copper powder, magnetically stirring at 140 ℃ for reaction for 12 hours, monitoring the reaction progress by TLC (i.e. thin layer chromatography), cooling to 40 ℃, filtering to remove excessive copper powder, adding 200g of an aqueous system to become turbid, extracting three times each time by 50g of ethyl acetate, merging organic phases, concentrating until the organic phases are dried to obtain 15.2g of light yellow crystalline solid 6, 7-dihydro-5H-pyrrolizin-3-yl (phenyl) ketone (specific structure confirmation map is shown in figures 1-3), and obtaining the product with the purity of 99.56% and the yield of 92%.
Adding 5g of 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) methanone into a 500ml single-port bottle, adding 50g of acetic acid, adding 20g of 20% potassium permanganate aqueous solution, controlling the temperature to 80 ℃, magnetically stirring for 6H, monitoring the reaction progress, cooling to 25 ℃, pouring into 200g of ice water, quenching the reaction, changing the system from reddish brown into reddish yellow suspension, adding 100g of dichloromethane each time for extraction for three times, merging organic phases for concentrating to dryness, adding 10g of ethyl acetate, heating to 50 ℃ for dissolving, slowly cooling for crystallization to-5 ℃, preserving the temperature for 2H, filtering and drying to obtain 4.66g of light yellow crystalline solid 5-benzoyl-2, 3-dihydropyrizine-1-one (specific structure confirmation map is shown in fig. 4-6), and obtaining the purity of 99.64%, and the yield of 87.5%.
Adding 4g of 5-benzoyl-2, 3-dihydropyrrolidin-1-one into a 500ml single-port bottle, adding 40g of methanol, adding 0.67g (1 eq.) of lithium aluminum hydride, magnetically stirring for 1H at normal temperature, monitoring the reaction progress by TLC, pouring into 100g of ice water to quench the reaction, adding 50g of ethyl acetate each time for extraction for three times, merging organic phases, concentrating to dryness, adding 10g of ethyl acetate, heating to 60 ℃ for dissolving, slowly cooling for crystallization to-10 ℃, preserving heat for 2H, filtering and drying to obtain 2.98g of light yellow crystalline solid (1 RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolididin-1-ol (specific structure confirmation map is shown in fig. 7-10), wherein the purity is 98.47%, and the yield is 74%.
Example 2
Taking 500ml of a single-port bottle, adding 20g of ketorolac, adding 100g of ethylene glycol, adding 6g of iron powder, magnetically stirring at 150 ℃ for reaction for 12 hours, monitoring the reaction progress by TLC, cooling to 40 ℃, filtering to remove excessive iron powder, adding 200g of a water system, turning turbid, extracting three times by 50g of ethyl acetate each time, combining organic phases, concentrating until the organic phases are dry to obtain 12.06g of light yellow crystalline solid 6, 7-dihydro-5H-pyrrolizin-3-yl (phenyl) ketone, wherein the purity is 99.43%, and the yield is 73%.
Adding 5g of 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) ketone into a 500ml single-port bottle, adding 50g of acetic acid, adding 20g of 20% high chromium trioxide aqueous solution, controlling the temperature to 70 ℃, magnetically stirring for 3H, monitoring the reaction progress by TLC, cooling to 25 ℃, pouring into 200g of ice water, quenching the reaction, changing the system from reddish brown into yellow suspension, adding 100g of dichloromethane each time for extraction for three times, merging organic phases for concentrating to dryness, adding 10g of ethyl acetate, heating to 50 ℃ for dissolving, slowly cooling for crystallization to-5 ℃, preserving the temperature for 2H, filtering and drying to obtain 4.26g of light yellow crystalline solid 5-benzoyl-2, 3-dihydropyrizine-1-ketone, wherein the purity is 99.37%, and the yield is 80%.
Adding 4g of 5-benzoyl-2, 3-dihydropyrrolidin-1-one into a 500ml single-port bottle, adding 40g of methanol, adding 0.53g (0.8 eq.) of sodium borohydride, magnetically stirring at normal temperature for 2H, after TLC monitoring reaction progress, pouring into 100g of ice water to quench reaction, adding 50g of ethyl acetate each time for extraction three times, merging organic phases, concentrating to dryness, adding 10g of ethyl acetate, heating to 60 ℃ for dissolving, slowly cooling for crystallization to-5 ℃, preserving heat for 2H, filtering and drying to obtain light yellow crystalline solid (1 RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizin-1-ol with 3.28g, purity 99.21% and yield 82%.
Example 3
Taking 500ml of a single-port bottle, adding 20g of ketorolac, adding 100g of paraxylene, adding 5g of copper powder, magnetically stirring and refluxing for 16H, monitoring the reaction progress, cooling to 40 ℃ after reaction, filtering to remove excessive copper powder, adding 200g of a water system, turning turbid, extracting three times by 50g of ethyl acetate each time, merging organic phases, concentrating to dryness to obtain 6.58g of light yellow crystalline solid 6, 7-dihydro-5H-pyrrolizin-3-yl (phenyl) methanone, wherein the purity is 99.24%, and the yield is 59%.
Adding 5g of 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) methanone into a 500ml single-port bottle, adding 50g of acetic acid, adding 20g of 20% ceric ammonium nitrate aqueous solution, controlling the temperature to 80 ℃, magnetically stirring for 3H, monitoring the reaction progress by TLC, cooling to 25 ℃, pouring into 200g of ice water, quenching the reaction, changing the system from reddish brown into yellow suspension, adding 100g of dichloromethane each time for extraction for three times, merging organic phases for concentrating to dryness, adding 10g of ethyl acetate, heating to 50 ℃ for dissolving, slowly cooling for crystallization to-5 ℃, preserving the temperature for 2H, filtering and drying to obtain 4.3g of light yellow crystalline solid 5-benzoyl-2, 3-dihydropyrrolizine-1-one, wherein the purity is 99.36%, and the yield is 81%.
Adding 4g of 5-benzoyl-2, 3-dihydropyrrolidin-1-one into a 500ml single-port bottle, adding 40g of methanol, adding 0.67g of sodium borohydride (1.0 eq.) and magnetically stirring for 1H at normal temperature, after TLC monitoring reaction progress, pouring into 100g of ice water to quench reaction, adding 50g of ethyl acetate each time for extraction three times, merging organic phases, concentrating to dryness, adding 10g of ethyl acetate, heating to 60 ℃ for dissolving, slowly cooling for crystallization to-10 ℃, preserving heat for 2H, filtering and drying to obtain light yellow crystalline solid (1 RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizin-1-ol with the purity of 3.63g and the yield of 90 percent.
Example 4
Taking 500ml of a single-port bottle, adding 20g of ketorolac, adding 100g of toluene, adding 5g of iron powder, magnetically stirring and refluxing for 12H, monitoring the reaction progress by TLC (thin layer chromatography), cooling to 40 ℃, filtering to remove excessive iron powder, adding 200g of a water system to become turbid, extracting three times by 50g of ethyl acetate each time, combining organic phases, concentrating until the organic phases are dry to obtain 6.6g of light yellow crystalline solid 6, 7-dihydro-5H-pyrrolizin-3-yl (phenyl) ketone, wherein the purity is 99.54%, and the yield is 40%.
Adding 5g of 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) ketone into a 500ml single-port bottle, adding 50g of acetic acid, adding 20g of 20% potassium permanganate aqueous solution, controlling the temperature to 80 ℃, magnetically stirring for 6H, monitoring the reaction progress by TLC, cooling to 25 ℃, pouring into 200g of ice water, quenching the reaction, changing the system from reddish brown into reddish yellow suspension, adding 100g of dichloromethane each time for extraction for three times, merging organic phases for concentrating to dryness, adding 10g of ethyl acetate, heating to 50 ℃ for dissolving, slowly cooling for crystallization to-5 ℃, preserving the temperature for 2H, filtering and drying to obtain light yellow crystalline solid 5-benzoyl-2, 3-dihydropyrrolizine-1-ketone with the purity of 4.6g and the yield of 86.3 percent.
Taking 500ml of a single-port bottle, adding 4g of 5-benzoyl-2, 3-dihydropyrrolidin-1-one, adding 40g of methanol, adding 1.34g (2 eq.) of lithium aluminum hydride, magnetically stirring for 1H at normal temperature, after TLC monitoring reaction progress, pouring into 100g of ice water to quench the reaction, adding 50g of ethyl acetate each time for extraction for three times, merging organic phases, concentrating to dryness, adding 10g of ethyl acetate, heating to 60 ℃ for dissolving, slowly cooling for crystallization to-10 ℃, preserving heat for 2H, filtering and drying to obtain 1.59g of light yellow crystalline solid (1 RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolididin-1-ol with purity of 99.51% and yield of 39.5%.
Comparative example 1
10g of ketorolac tromethamine is added into a 500ml single-port bottle, 18.5g of potassium permanganate is added, 20ml of 0.1mol/L potassium hydroxide solution is added, and the mixture is stirred at 26 ℃ for reaction for 4 hours. TLC thin layer chromatography analysis of large amounts of starting material remained, only small amounts of (1 RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizin-1-ol. The mixture was separated, purified and concentrated by column chromatography to obtain 0.05g of pale yellow solid.
As can be seen from comparative example 1, the yield of the final product ((1 RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizin-1-ol) obtained by the above method is low, and the separation process is complicated by column separation.
Comparative example 2
5g ketorolac is taken and added with 15mL anhydrous N, N-dimethylformamide and 0.3g FeCl 3 The reaction is carried out for 12 hours under the oxygen atmosphere and the temperature of 110 ℃. TLC analysis, the basic reaction was complete with more byproducts. The reaction solution was cooled to room temperature, filtered and concentrated to dryness under reduced pressure. Adding 10g of ethyl acetate, heating to 50 ℃ for dissolution, slowly cooling for crystallization to-5 ℃, preserving heat for 2 hours, filtering and drying to obtain 2.3g of yellow brown sticky solid 5-benzoyl-2, 3-dihydropyrrolizine-1-ketone, wherein the yield is 52.1 percent and the purity is 85.26 percent.
As can be seen from comparative example 2, the purity of 5-benzoyl-2, 3-dihydropyrrolidin-1-one obtained by direct crystallization is low, the quality requirement of impurity contrast quality is not met, and the operation is not simple enough because the process is carried out in an anhydrous environment.
Comparative example 3
5g ketorolac was taken and 15mL of undehydrated N, N-dimethylformamide, 0.3g FeCl was added 3 The reaction is carried out for 12 hours under the oxygen atmosphere and the temperature of 110 ℃. TLC analysis, a large amount of starting material remained, unreacted completely.
This comparative example, in combination with comparative example 2, shows that the presence of water in the reaction environment results in insufficient reaction, and is of no practical value.
The above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be appreciated by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims (8)
1. A method for preparing ketorolac or related impurities of a salt thereof, comprising the steps of:
(1) Adding a metal catalyst into an organic solvent by taking ketorolac or ketorolac as an initial raw material, filtering the rest metal catalyst after the reaction is finished, and crystallizing to obtain 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) ketone; the metal catalyst is copper powder or iron powder;
(2) Dissolving 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) ketone with a solvent, oxidizing by an oxidant, and crystallizing to obtain 5-benzoyl-2, 3-dihydropyrrolizine-1-ketone; the oxidant is one or a mixture of any more of hydrogen peroxide, nitric acid, potassium permanganate, ammonium cerium nitrate, potassium dichromate and chromium trioxide;
(3) Adding 5-benzoyl-2, 3-dihydro-pyrrolizine-1-one into a polar solvent, reducing the mixture by using a reducing agent, and crystallizing the mixture to obtain (1 RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-ol; the reducing agent is one or a mixture of a plurality of lithium aluminum hydride, sodium borohydride and aluminum isopropoxide; the mol ratio of the 5-benzoyl-2, 3-dihydropyrrolidin-1-one to the reducing agent is 1:0.8-1:1.0;
the overall reaction equation is as follows:
2. the preparation method according to claim 1, wherein the temperature in the metal catalysis process is 90-180 ℃ and the reaction time is 4-18 h.
3. The method of claim 2, wherein the temperature during metal catalysis is 120 ℃ to 150 ℃.
4. The preparation method according to claim 1, wherein in the step (2), the reaction time is 0.5 to 6 hours by oxidizing with an oxidizing agent at 35 to 95 ℃.
5. The process according to claim 4, wherein the oxidation is carried out by an oxidizing agent at 70 to 80 ℃.
6. The process according to any one of claims 1 to 5, wherein in step (1), the organic solvent is toluene, p-xylene, N-methylpyrrolidone, dimethylacetamide, dimethylformamide, dimethylsulfoxide, ethylene glycol, butanol, or a mixture of any one or more thereof.
7. The process according to any one of claims 1 to 5, wherein in step (2), the molar ratio of 6, 7-dihydro-5H-pyrrolizin-3-yl (phenyl) methanone to oxidant is from 1:1 to 1:10.
8. The process according to any one of claims 1 to 5, wherein in step (3), the reduction reaction time is 1 to 6 hours and the reaction temperature is-20 to 80 ℃.
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