CN114181215A - Preparation method of related impurities of ketorolac or ketorolac salt - Google Patents
Preparation method of related impurities of ketorolac or ketorolac salt Download PDFInfo
- Publication number
- CN114181215A CN114181215A CN202111614113.7A CN202111614113A CN114181215A CN 114181215 A CN114181215 A CN 114181215A CN 202111614113 A CN202111614113 A CN 202111614113A CN 114181215 A CN114181215 A CN 114181215A
- Authority
- CN
- China
- Prior art keywords
- ketorolac
- benzoyl
- dihydro
- preparation
- ketone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 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 33
- 229960004752 ketorolac Drugs 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 239000012535 impurity Substances 0.000 title claims description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- 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 26
- 238000001914 filtration 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 17
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 239000007800 oxidant agent Substances 0.000 claims abstract description 13
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 239000007858 starting material Substances 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 239000002798 polar solvent Substances 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 20
- 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 description 17
- 239000000203 mixture Substances 0.000 claims description 17
- -1 6, 7-dihydro-5H-pyrrolizin-3-yl (phenyl) Chemical group 0.000 claims description 16
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 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
- 230000035484 reaction time Effects 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
- 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
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 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
- 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 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 238000006722 reduction reaction Methods 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims 1
- 239000006227 byproduct Substances 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 2
- 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 16
- 239000007787 solid Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
- 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 12
- 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
- 238000012544 monitoring process Methods 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 11
- 238000001035 drying Methods 0.000 description 10
- 238000010791 quenching Methods 0.000 description 10
- 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
- 229960004384 ketorolac tromethamine Drugs 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 239000000243 solution Substances 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
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000001228 spectrum Methods 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
- 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
- 239000013558 reference substance Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- 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
- 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
- 239000000047 product Substances 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000000926 separation method Methods 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
- 238000009835 boiling Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000007689 inspection Methods 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
- 229940094443 oxytocics prostaglandins 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
Images
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 related substances of ketorolac or ketorolac salts, which comprises the following steps: taking ketorolac or ketorolac salt as a starting material, adding a metal catalyst into an organic solvent, filtering out the residual 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 in a solvent, oxidizing by an oxidant, and crystallizing to obtain 5-benzoyl-2, 3-dihydropyrrolizine-1-ketone; adding 5-benzoyl-2, 3-dihydropyrrolizine-1-ketone into a polar solvent, reducing by using a reducing agent, and crystallizing to obtain (1RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-alcohol. The method has the advantages of simple operation, convenient and easily obtained raw materials and total yield of over 70 percent. Compared with the preparation method in the prior art, the preparation method has the advantages of few byproducts, remarkably increased yield, simple and convenient preparation method, and capability of obtaining related substances with high purity and high yield without complicated and harsh conditions.
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 ketorolac salts.
Background
Ketorolac tromethamine is a non-steroidal anti-inflammatory drug, can inhibit the biosynthesis of prostaglandins, has an analgesic effect, and has no sedative or anxiolytic effect, so that ketorolac tromethamine is widely applied to perioperative analgesia. The quality standards of the controller products are recorded in the United States Pharmacopoeia (USP)43 edition and the European Pharmacopoeia (EP)10.0 edition.
In the process of examining the product quality research, it is found that the pharmacopoeia of various countries includes a plurality of related substances, including (1RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizin-1-ol (EP10.0 version impurity a), 6, 7-dihydro-5H-pyrrolizin-3-yl (phenyl) methanone (EP10.0 version impurity I), and 5-benzoyl-2, 3-dihydropyrrolizin-1-one (EP10.0 version impurity B), and it is necessary to control related impurities, and the related impurities are difficult to obtain as a reference substance, thus the research and detection of related impurities of ketorolac tromethamine are seriously influenced.
At present, the preparation methods of (1RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-ol (EP10.0 version impurity A), 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) ketone (EP10.0 version impurity I) and 5-benzoyl-2, 3-dihydropyrrolizine-1-ketone (EP10.0 version impurity B) are reported at home and abroad. Potassium permanganate is added into ketorolac tromethamine to form (1RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-alcohol (EP10.0 version impurity A) in an alkaline solvent in foreign countries, but the recovery rate is not high, in addition, column separation is needed, and the reaction process is complicated. In addition, a polar solvent and ferric trichloride are added into ketorolac abroad, the ketorolac reacts in an oxygen atmosphere, and 5-benzoyl-2, 3-dihydropyrrolizine-1-one (EP10.0 version impurity B) is obtained through multi-step reaction.
Disclosure of Invention
The embodiment of the invention provides a preparation method of related impurities of ketorolac or salts thereof, and particularly relates to a preparation method of (1RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizin-1-ol (EP10.0 version impurity A), 6, 7-dihydro-5H-pyrrolizin-3-yl (phenyl) methanone (EP10.0 version impurity I) and 5-benzoyl-2, 3-dihydropyrrolizin-1-one (EP10.0 version impurity B), aiming at efficiently and simply obtaining a high-purity impurity reference substance for researching and detecting related impurities of ketorolac tromethamine.
The technical scheme adopted by the invention comprises the following steps:
(1) taking ketorolac or ketorolac salt as a starting material, adding a metal catalyst into an organic solvent, filtering out the residual metal catalyst after the reaction is finished, and crystallizing to obtain 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) ketone;
(2) dissolving 6, 7-dihydro-5H-pyrrolizin-3-yl (phenyl) ketone in a solvent, oxidizing by an oxidant, and crystallizing to obtain 5-benzoyl-2, 3-dihydropyrrolizin-1-one;
(3) adding 5-benzoyl-2, 3-dihydropyrrolizine-1-ketone into a polar solvent, reducing by using a reducing agent, and crystallizing to obtain (1RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-alcohol.
Preferably, the metal catalyst is copper powder or iron powder, more preferably copper powder. Compared with other metal catalysts, the copper powder or iron powder is added, so that the selectivity is improved, the byproducts are reduced, and the yield of the 6, 7-dihydro-5H-pyrrolizin-3-yl (phenyl) ketone is greatly improved.
Preferably, the temperature in the metal catalysis process is 90-180 ℃, and the reaction time is 4-18 h. Furthermore, the temperature in the metal catalysis process is selected to be 120-150 ℃, and the catalytic efficiency of the metal catalyst is higher at the temperature.
Preferably, in the step (2), the reaction is carried out for 0.5-6 h by oxidizing with an oxidant at 30-95 ℃. Further, the oxidation reaction is carried out by an oxidant at the temperature of 70-80 ℃, and the oxidation reaction is more complete at the temperature.
Preferably, in the step (1), the organic solvent is one or a mixture of any more of toluene, p-xylene, N-methylpyrrolidone, dimethylacetamide, dimethylformamide, dimethyl sulfoxide, ethylene glycol and butanol. N-methylpyrrolidone, dimethylacetamide, dimethylformamide, dimethylsulfoxide, ethylene glycol, and butanol are preferable, and the yield can be remarkably improved by using a high-boiling strongly polar organic solvent, for example, dimethylformamide, ethylene glycol, or the like.
Preferably, in 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 the step (2), the oxidant can be one or a mixture of any more of hydrogen peroxide, nitric acid, potassium permanganate, cerium ammonium nitrate, potassium dichromate and 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 molar ratio of the 5-benzoyl-2, 3-dihydropyrrolizine-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 ℃. Preferably, the equivalent of the reducing agent is selected to be 0.8-1.0, and the yield is greatly influenced if the equivalent is exceeded.
In some embodiments of the present invention, acetic acid may be further added to the reaction system in the step (2) to promote the reaction. The amount of the acetic acid may be 10 times the mass of the reaction substrate of the step (2).
Certain embodiments of the present invention provide a method for preparing impurities associated with ketorolac or a salt thereof, the method comprising the steps of:
(1) taking ketorolac or ketorolac salt as a starting material, adding a metal catalyst into an organic solvent, filtering out the residual metal catalyst after the reaction is finished, extracting, separating and purifying to obtain 6, 7-dihydro-5H-pyrrolizin-3-yl (phenyl) ketone;
(2) dissolving 6, 7-dihydro-5H-pyrrolizin-3-yl (phenyl) ketone in a solvent, oxidizing by an oxidant at 70-80 ℃, sequentially quenching, extracting, combining organic phases, concentrating to be dry, crystallizing, filtering and drying after the reaction is finished to obtain 5-benzoyl-2, 3-dihydropyrrolizin-1-one;
(3) adding 5-benzoyl-2, 3-dihydropyrrolizine-1-ketone into a polar solvent, reducing by using a reducing agent, quenching, extracting and combining organic phases in sequence after the reaction is finished, and concentrating to dry and crystallize to obtain (1RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-ol.
In the step (1), the ketorolac salt can be 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 as a starting material. The metal catalyst is copper powder, iron powder and the like. The organic solvent is one or a mixture of any more of toluene, p-xylene, pyridine, dimethylformamide, dimethyl sulfoxide, ethylene glycol and butanol. The reaction temperature is 120-150 ℃, the reaction time is 4-18 h, and the concentration and crystallization temperature is-10 ℃.
In the step (2), the oxidant can be one or a mixture of any more of hydrogen peroxide, nitric acid, potassium permanganate, ammonium ceric 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 in the oxidation reaction process is 30-95 ℃, 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 in the step (2), and the mass of the acetic acid can be 10 times of that of the 6, 7-dihydro-5H-pyrrolizin-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 molar ratio of the 5-benzoyl-2, 3-dihydropyrrolizine-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 whole reaction equation is as follows:
the invention has the beneficial effects that:
(1) the invention provides a brand-new method for preparing ketorolac or related impurities of ketorolac salts, which has the advantages of simple operation, convenient and easily obtained raw materials and total yield of more than 70 percent. The purity of the prepared (1RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-alcohol reaches more than 98 percent, the purity of 5-benzoyl-2, 3-dihydropyrrolizine-1-ketone reaches more than 99 percent, and the purity of 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) ketone reaches more than 99 percent, which all meet the requirements of serving as an impurity reference substance and play a positive role in the research and inspection of related impurities of ketorolac tromethamine.
(2) Compared with the preparation method in the prior art, the preparation method has the advantages of few byproducts, remarkably increased yield, simple and convenient preparation method, and capability of obtaining related substances with high purity and high yield without complicated and harsh conditions.
Drawings
FIG. 1 is a mass spectrum of an 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 is 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 the intermediate 5-benzoyl-2, 3-dihydropyrrolizine-1-one of example 1 of the present invention.
FIG. 5 is a chromatogram of the intermediate 5-benzoyl-2, 3-dihydropyrrolizin-1-one of example 1 of the present invention.
FIG. 6 is the hydrogen spectrum of the intermediate 5-benzoyl-2, 3-dihydropyrrolizine-1-one of example 1 of the present invention.
FIG. 7 shows the mass spectrum of (1RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-ol in example 1 of the present invention.
FIG. 8 is a hydrogen spectrum of (1RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-ol of example 1 of the present invention.
FIG. 9 shows a carbon spectrum of (1RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-ol in example 1 of the present invention.
FIG. 10 is a chromatogram of (1RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizine-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 clearer, the present invention will be described in further detail below with reference to the accompanying drawings, but embodiments of the present invention are not limited thereto.
Example 1
Adding 20g of ketorolac into a 500ml single-neck bottle, adding 100g of DMF (dimethyl formamide), adding 5g of copper powder, magnetically stirring at 140 ℃ for reaction for 12 hours, monitoring the reaction process by TLC (thin-layer chromatography), cooling to 40 ℃, filtering to remove excessive copper powder, adding 200g of water system to become turbid, extracting with 50g of ethyl acetate for three times each time, combining 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 (the specific structure confirms that the map is shown in the figure 1-3), wherein the purity is 99.56 percent and the yield is 92 percent.
Adding 5g of 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) ketone into a 500ml single-neck bottle, adding 50g of acetic acid, adding 20g of 20% potassium permanganate aqueous solution, controlling the temperature to be 80 ℃, magnetically stirring for 6H, monitoring the reaction process by TLC, cooling to 25 ℃, pouring into 200g of ice water to quench the reaction, changing the system from reddish brown to reddish yellow suspension, adding 100g of dichloromethane for extraction for three times, combining organic phases, concentrating to dryness, adding 10g of ethyl acetate, heating to 50 ℃ for dissolution, slowly cooling to-5 ℃, keeping the temperature for 2H, filtering and drying to obtain 4.66g of light yellow crystalline solid 5-benzoyl-2, 3-dihydropyrrolizine-1-ketone (the specific structure is confirmed to be shown in figures 4-6), the purity is 99.64%, the yield thereof was found to be 87.5%.
Adding 4g of 5-benzoyl-2, 3-dihydropyrrolizine-1-one into a 500ml single-neck bottle, adding 40g of methanol, adding 0.67g (1eq.) 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, extracting for three times, combining organic phases, concentrating to dryness, adding 10g of ethyl acetate, heating to 60 ℃ for dissolution, slowly cooling to-10 ℃, keeping the temperature for 2H, filtering and drying to obtain 2.98g of light yellow crystalline solid (1RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-ol (the specific structure is confirmed to be in figures 7-10), wherein the purity is 98.47%, and the yield is 74%.
Example 2
Adding 20g of ketorolac into a 500ml single-mouth bottle, adding 100g of ethylene glycol, adding 6g of iron powder, magnetically stirring at 150 ℃ for reaction for 12 hours, monitoring the reaction process by TLC (thin layer chromatography), cooling to 40 ℃, filtering to remove excessive iron powder, adding 200g of water system to become turbid, extracting with 50g of ethyl acetate for three times, combining organic phases, and concentrating until the organic phases are dried to obtain 12.06g of light yellow crystalline solid 6, 7-dihydro-5H-pyrrolizin-3-yl (phenyl) ketone with purity of 99.43 percent and yield of 73 percent.
Adding 5g of 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) ketone into a 500ml single-neck bottle, adding 50g of acetic acid, adding 20g of 20% aqueous solution of high chromium trioxide, controlling the temperature to be 70 ℃, magnetically stirring for 3H, monitoring the reaction process by TLC, cooling to 25 ℃, pouring into 200g of ice water to quench the reaction, changing the system from reddish brown to yellow suspension, adding 100g of dichloromethane for extraction for three times, combining organic phases, concentrating to dryness, adding 10g of ethyl acetate, heating to 50 ℃ for dissolution, slowly cooling to-5 ℃, preserving the temperature for 2H, filtering and drying to obtain 4.26g of light yellow crystalline solid 5-benzoyl-2, 3-dihydropyrrolizine-1-one, the purity is 99.37%, and the yield is 80%.
Adding 4g of 5-benzoyl-2, 3-dihydropyrrolizine-1-one into a 500ml single-neck bottle, adding 40g of methanol, adding 0.53g (0.8eq.) of sodium borohydride, magnetically stirring at normal temperature for 2H, 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, extracting for three times, combining organic phases, concentrating to dryness, adding 10g of ethyl acetate, heating to 60 ℃ for clearing, slowly cooling to-5 ℃, keeping the temperature for 2H, filtering and drying to obtain a light yellow crystalline solid (1RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-ol, wherein the purity is 99.21 percent and the yield is 82 percent.
Example 3
Adding 20g of ketorolac into a 500ml single-mouth bottle, adding 100g of p-xylene, adding 5g of copper powder, magnetically stirring and refluxing for 16H, monitoring the reaction process by TLC (thin layer chromatography), cooling to 40 ℃, filtering to remove excessive copper powder, adding 200g of water system to become turbid, extracting with 50g of ethyl acetate for three times, combining organic phases, and concentrating until the mixture is dry to obtain 6.58g of light yellow crystalline solid 6, 7-dihydro-5H-pyrrolizin-3-yl (phenyl) ketone, wherein the purity is 99.24 percent, and the yield is 59 percent.
Adding 5g of 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) ketone into a 500ml single-neck bottle, adding 50g of acetic acid, adding 20g of 20% ammonium ceric nitrate aqueous solution, controlling the temperature to be 80 ℃, magnetically stirring for 3H, monitoring the reaction process by TLC, cooling to 25 ℃, pouring into 200g of ice water to quench the reaction, changing the system from reddish brown to yellow suspension, adding 100g of dichloromethane for extraction for three times, combining organic phases, concentrating to be dry, adding 10g of ethyl acetate, heating to 50 ℃ for clearing, slowly cooling 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-ketone, wherein the purity is 99.36%, and the yield is 81%.
Adding 4g of 5-benzoyl-2, 3-dihydropyrrolizine-1-one into a 500ml single-neck bottle, adding 40g of methanol, adding 0.67g (1.0eq.) of sodium borohydride, magnetically stirring at normal temperature for 1H, 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, extracting for three times, combining organic phases, concentrating to dryness, adding 10g of ethyl acetate, heating to 60 ℃ for clearing, slowly cooling to-10 ℃, keeping the temperature for 2H, filtering and drying to obtain 3.63g of light yellow crystalline solid (1RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-alcohol with the purity of 99.45 percent and the yield of 90 percent.
Example 4
Adding 20g of ketorolac into a 500ml single-mouth bottle, adding 100g of toluene, adding 5g of iron powder, magnetically stirring and refluxing for 12H, monitoring the reaction process by TLC (thin-layer chromatography), cooling to 40 ℃, filtering to remove excessive iron powder, adding 200g of water system to become turbid, extracting with 50g of ethyl acetate for three times, combining organic phases, and concentrating until the organic phases are dried to obtain 6.6g of light yellow crystalline solid 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) ketone with the purity of 99.54 percent and the yield of 40 percent.
Adding 5g of 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) ketone into a 500ml single-neck bottle, adding 50g of acetic acid, adding 20g of 20% potassium permanganate aqueous solution, controlling the temperature to be 80 ℃, magnetically stirring for 6H, monitoring the reaction process by TLC, cooling to 25 ℃, pouring into 200g of ice water to quench the reaction, changing the system from reddish brown to reddish yellow suspension, adding 100g of dichloromethane for extraction for three times, combining organic phases, concentrating to be dry, adding 10g of ethyl acetate, heating to 50 ℃ for dissolution, slowly cooling to-5 ℃, keeping the temperature for 2H, filtering and drying to obtain 4.6g of light yellow crystalline solid 5-benzoyl-2, 3-dihydropyrrolizine-1-ketone, wherein the purity is 99.11%, and the yield is 86.3%.
Adding 4g of 5-benzoyl-2, 3-dihydropyrrolizine-1-one into a 500ml single-neck bottle, adding 40g of methanol, adding 1.34g (2eq.) 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, extracting for three times, combining organic phases, concentrating to dryness, adding 10g of ethyl acetate, heating to 60 ℃ for clearing, slowly cooling to-10 ℃, keeping the temperature for 2H, filtering and drying to obtain 1.59g of light yellow crystalline solid (1RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-ol, the purity is 99.51%, and the yield is 39.5%.
Comparative example 1
And (3) adding 10g of ketorolac tromethamine into a 500mL single-neck bottle, adding 18.5g of potassium permanganate, adding 20mL of 0.1mol/L potassium hydroxide solution, and stirring and reacting for 4 hours at 26 ℃. TLC thin layer chromatography analysis, a large amount of starting material remained, only a small amount of (1RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizidin-1-ol. The mixture is separated, purified and concentrated to be dry by column chromatography to obtain 0.05g of light yellow solid.
As can be seen from comparative example 1, the final product ((1RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-ol) obtained by the above method has a low yield, and requires column separation, which is complicated.
Comparative example 2
Taking 5g of ketorolac, adding 15mL of anhydrous N, N-dimethylformamide and 0.3g of FeCl3And heating the mixture at 110 ℃ in an oxygen atmosphere to react for 12 hours. TLC analysis shows that the reaction is basically complete and the side products are more. 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 2h, 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 the comparative example 2, the 5-benzoyl-2, 3-dihydropyrrolizin-1-one obtained by direct crystallization has low purity, does not meet the quality requirement of impurity control, needs to be carried out in an anhydrous environment and is not easy to operate.
Comparative example 3
Taking 5g of ketorolac, adding 15mL of non-dehydrated N, N-dimethylformamide and 0.3g of FeCl3And heating the mixture at 110 ℃ in an oxygen atmosphere to react for 12 hours. TLC analysis, a large amount of starting material remained and the reaction was not complete.
As can be seen from the comparison example in combination with the comparison example 2, when water exists in the reaction environment, the reaction is insufficient, and the practical value is not realized.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.
Claims (10)
1. A process for the preparation of ketorolac or its salt related impurities comprising the steps of:
(1) taking ketorolac or ketorolac salt as a starting material, adding a metal catalyst into an organic solvent, filtering out the residual metal catalyst after the reaction is finished, and crystallizing to obtain 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) ketone;
(2) dissolving 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) ketone in a solvent, oxidizing by an oxidant, and crystallizing to obtain 5-benzoyl-2, 3-dihydropyrrolizine-1-ketone;
(3) adding 5-benzoyl-2, 3-dihydropyrrolizine-1-ketone into a polar solvent, reducing by using a reducing agent, and crystallizing to obtain (1RS) -5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-alcohol.
2. The method according to claim 1, wherein the metal catalyst is copper powder or iron powder.
3. The preparation method of claim 2, wherein the temperature in the metal catalysis process is 90-180 ℃ and the reaction time is 4-18 h.
4. The method of claim 3, wherein the temperature during the metal catalysis is 120 ℃ to 150 ℃.
5. The preparation method according to claim 1, wherein in the step (2), the mixture is oxidized by the oxidant at 35-95 ℃ for 0.5-6 h.
6. The preparation method according to claim 5, wherein the oxidation is carried out at 70-80 ℃.
7. The method according to any one of claims 1 to 6, wherein in the step (1), the organic solvent is one or a mixture of any more of toluene, p-xylene, N-methylpyrrolidone, dimethylacetamide, dimethylformamide, dimethylsulfoxide, ethylene glycol and butanol.
8. The preparation method according to any one of claims 1 to 6, wherein in the step (2), the oxidizing agent is one or a mixture of any more of hydrogen peroxide, nitric acid, potassium permanganate, ceric ammonium nitrate, potassium dichromate and chromium trioxide; the molar ratio of the 6, 7-dihydro-5H-pyrrolizin-3-yl (phenyl) to the oxidant is 1: 1-1: 10.
9. The preparation method according to any one of claims 1 to 6, wherein 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 molar ratio of the 5-benzoyl-2, 3-dihydropyrrolizine-1-one to the reducing agent is 1: 0.8-1: 1.5; the reduction reaction time is 1-6 h, and the reaction temperature is-20-80 ℃.
10. The method according to claim 9, wherein the equivalent of the reducing agent is 0.8 to 1.0.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111614113.7A CN114181215B (en) | 2021-12-27 | 2021-12-27 | Preparation method of ketorolac or related impurities of ketorolac salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111614113.7A CN114181215B (en) | 2021-12-27 | 2021-12-27 | Preparation method of ketorolac or related impurities of ketorolac salt |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114181215A true CN114181215A (en) | 2022-03-15 |
| CN114181215B CN114181215B (en) | 2024-03-01 |
Family
ID=80606101
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111614113.7A Active CN114181215B (en) | 2021-12-27 | 2021-12-27 | Preparation method of ketorolac or related impurities of ketorolac salt |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114181215B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6197976B1 (en) * | 1998-12-14 | 2001-03-06 | Syntex (U.S.A.) Llc | Preparation of ketorolac |
| CN109400600A (en) * | 2018-12-18 | 2019-03-01 | 四川仁安药业有限责任公司 | The novel preparation method of 10 α-methoxyl group -9,10- dihydro lysergol |
| CN112898307A (en) * | 2021-02-07 | 2021-06-04 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | Ketorolac impurity C and preparation method and application thereof |
| CN113045471A (en) * | 2021-03-19 | 2021-06-29 | 四川尚锐生物医药有限公司 | Improved ketorolac intermediate preparation method |
| CN113087626A (en) * | 2020-01-09 | 2021-07-09 | 鲁南制药集团股份有限公司 | Ketorolac tromethamine intermediate compound VI |
-
2021
- 2021-12-27 CN CN202111614113.7A patent/CN114181215B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6197976B1 (en) * | 1998-12-14 | 2001-03-06 | Syntex (U.S.A.) Llc | Preparation of ketorolac |
| CN109400600A (en) * | 2018-12-18 | 2019-03-01 | 四川仁安药业有限责任公司 | The novel preparation method of 10 α-methoxyl group -9,10- dihydro lysergol |
| CN113087626A (en) * | 2020-01-09 | 2021-07-09 | 鲁南制药集团股份有限公司 | Ketorolac tromethamine intermediate compound VI |
| CN112898307A (en) * | 2021-02-07 | 2021-06-04 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | Ketorolac impurity C and preparation method and application thereof |
| CN113045471A (en) * | 2021-03-19 | 2021-06-29 | 四川尚锐生物医药有限公司 | Improved ketorolac intermediate preparation method |
Non-Patent Citations (1)
| Title |
|---|
| 庞冀燕, 孙光, 傅德才, 张守芳: "二氢吡咯并吡嗪酮衍生物的合成和抗炎镇痛作用", 中国药物化学杂志, no. 02, 20 April 2002 (2002-04-20), pages 82 - 85 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114181215B (en) | 2024-03-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104250232A (en) | Preparation method of parecoxib sodium | |
| CN112778147B (en) | Preparation method of 2-amino-3-methyl-5-chlorobenzoic acid | |
| AU2013274407A1 (en) | Improved method of preparing oxymorphone | |
| CN114181215B (en) | Preparation method of ketorolac or related impurities of ketorolac salt | |
| CN108409626A (en) | The preparation method of ovarian cancer resistance medicament Rucaparib key intermediates | |
| CN115417797B (en) | Preparation method of bifenazate | |
| CN114369099B (en) | Method for preparing pyromellitic dianhydride by liquid-phase oxidation | |
| CN113979937B (en) | Method for preparing substituted aromatic heterocyclic compound from aromatic heterocyclic compound | |
| CN107880004B (en) | Preparation method of 5-phenoxyphthalide | |
| CN102766024B (en) | The preparation method of difluoroethanol | |
| CN110684019B (en) | Preparation method of ticagrelor intermediate oxide impurity | |
| CN114478243A (en) | Method for synthesizing dihydroxy dimethyl terephthalate by oxygen catalytic oxidation method | |
| CN110128246B (en) | Preparation method of hydroxytyrosol | |
| CN113979888A (en) | Method for preparing N, N, N-trineovalerylated-1, 3, 5-triaminobenzene | |
| CN108218708B (en) | Preparation method and application of 5-chloro-4-methyl-2-nitrobenzoic acid | |
| CN107573301B (en) | Preparation method of tricyclazole intermediate | |
| CN107628947B (en) | Preparation method of pemetrexed disodium key intermediate | |
| CN114478413B (en) | Preparation method and application of 2- (2 ' -hydroxy-3 ' -methallyl-5 ' -methylphenyl) benzotriazole | |
| CN114890902B (en) | Preparation method of 2-methyl-3-trifluoromethyl aniline | |
| CN111138445B (en) | Method for preparing 5, 12-dioxaanthracene-6, 11-diketone compound by nickel catalysis | |
| CN101428772A (en) | Separation purification method for green nitrating agent nitrogen pentoxide | |
| CN101648912A (en) | Continuous preparation method of 4-nitro-3,5-dimethylpyridine-N-oxide | |
| CN117903069A (en) | Synthesis method of fampicin intermediate 2-bromo-5-chloropyrazine | |
| CN117903097A (en) | Recovery method of tergolian key intermediate mother liquor | |
| CN114907380A (en) | Synthetic method of isothiazolo [5,4-B ] pyridine-3 (2H) -ketone 1, 1-dioxide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |