CN114539155B - Preparation of edaravone - Google Patents
Preparation of edaravone Download PDFInfo
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- CN114539155B CN114539155B CN202210139202.9A CN202210139202A CN114539155B CN 114539155 B CN114539155 B CN 114539155B CN 202210139202 A CN202210139202 A CN 202210139202A CN 114539155 B CN114539155 B CN 114539155B
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- edaravone
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- phenylhydrazine
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- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical compound O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 229950009041 edaravone Drugs 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- 239000010949 copper Substances 0.000 claims abstract description 6
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000000654 additive Substances 0.000 claims abstract description 5
- 229910052802 copper Inorganic materials 0.000 claims abstract description 5
- 230000000996 additive effect Effects 0.000 claims abstract description 4
- 239000003513 alkali Substances 0.000 claims abstract description 4
- 230000009471 action Effects 0.000 claims abstract description 3
- 238000005859 coupling reaction Methods 0.000 claims abstract description 3
- -1 furan-2-ylmethyl Chemical group 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 5
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 4
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 claims description 2
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 abstract description 10
- 229940067157 phenylhydrazine Drugs 0.000 abstract description 10
- 231100000024 genotoxic Toxicity 0.000 abstract description 6
- 230000001738 genotoxic effect Effects 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 150000001555 benzenes Chemical class 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 4
- 206010008118 cerebral infarction Diseases 0.000 description 4
- 208000026106 cerebrovascular disease Diseases 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 150000004031 phenylhydrazines Chemical class 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- DOPJNPGPZIJGEZ-UHFFFAOYSA-N 5-methylpyrazol-3-one Chemical compound CC1=CC(=O)N=N1 DOPJNPGPZIJGEZ-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- OTCCIMWXFLJLIA-UHFFFAOYSA-N N-acetyl-DL-aspartic acid Natural products CC(=O)NC(C(O)=O)CC(O)=O OTCCIMWXFLJLIA-UHFFFAOYSA-N 0.000 description 3
- OTCCIMWXFLJLIA-BYPYZUCNSA-N N-acetyl-L-aspartic acid Chemical compound CC(=O)N[C@H](C(O)=O)CC(O)=O OTCCIMWXFLJLIA-BYPYZUCNSA-N 0.000 description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000003760 magnetic stirring Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 206010060860 Neurological symptom Diseases 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 2
- 229940112669 cuprous oxide Drugs 0.000 description 2
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- NOSYGNWELJYIQH-UHFFFAOYSA-N n,n'-bis(thiophen-2-ylmethyl)oxamide Chemical compound C=1C=CSC=1CNC(=O)C(=O)NCC1=CC=CS1 NOSYGNWELJYIQH-UHFFFAOYSA-N 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000005808 2,4,6-trimethoxyphenyl group Chemical group [H][#6]-1=[#6](-[#8]C([H])([H])[H])-[#6](-*)=[#6](-[#8]C([H])([H])[H])-[#6]([H])=[#6]-1-[#8]C([H])([H])[H] 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229940123457 Free radical scavenger Drugs 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- ZKXWKVVCCTZOLD-FDGPNNRMSA-N copper;(z)-4-hydroxypent-3-en-2-one Chemical compound [Cu].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O ZKXWKVVCCTZOLD-FDGPNNRMSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 231100000089 gene mutation induction Toxicity 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
- C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
- C07D231/26—1-Phenyl-3-methyl-5- pyrazolones, unsubstituted or substituted on the phenyl ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for preparing edaravone. Specifically, halogenated benzene and 3-methylpyrazole-5-ketone undergo a coupling reaction under the action of a copper reagent/alkali/additive to prepare edaravone. The preparation method can avoid the use of phenylhydrazine genotoxic compounds.
Description
Technical Field
The invention relates to the field of chemical synthesis, and relates to preparation of edaravone.
Background
Edaravone is a brain protectant (free radical scavenger). Clinical studies suggest that N-acetylaspartic acid (NAA) is a specific marker of surviving nerve cells and that the initial level of cerebral infarction is drastically reduced. Edaravone is given to patients in the acute stage of cerebral infarction, so that the reduction of local cerebral blood flow around the infarction can be inhibited, and the NAA content in the brain after the onset of the disease is obviously increased compared with that of a glycerol control group. Preclinical studies suggest that intravenous edaravone administration in rats after ischemia/ischemia reperfusion can prevent the progression of cerebral edema and cerebral infarction, and alleviate the accompanying neurological symptoms, inhibiting delayed neuronal death. The mechanism research shows that edaravone can remove free radicals and inhibit lipid peroxidation, so that oxidative damage of brain cells, vascular endothelial cells and nerve cells is inhibited. The medicine is developed by Mitsubishi field edge pharmaceutical company in Japan, is marketed in Japan in 6 th year 2001, and a plurality of imitation medicines are marketed in China at present. Edaravone is currently mainly used for treating neurological symptoms related to the acute phase of cerebral infarction; new indication Amyotrophic Lateral Sclerosis (ALS) was approved in japan 6 months 2015; U.S. 5a 2017 approves use for edaravone treatment of ALS.
Edaravone has the chemical name of 3-methyl-1-phenyl-2-pyrazoline-5-ketone and the chemical structure as follows:
At present, the synthesis of edaravone is reported in a plurality of patents and literature. A series of patents (CN 109608398A, WO200616707, CN 113072502A, US200527120, etc.) and literature (J.org.chem., 2008,73,9075-9083;Tet rahedron,2009,65,9592-9697; org.Biomol.chem.2016,14,6996-7000, etc.) disclose general methods for preparing edaravone, phenylhydrazine being reacted with ethyl acetoacetate. The reaction is usually carried out in an alcohol solvent or water as a solvent, and the reaction is reported to be carried out directly by taking acetic acid and the like as solvents, so that the reaction is relatively intense. The synthetic route is as follows:
Although the method for synthesizing edaravone can prepare the product, the method has great defects in controlling and improving the quality of the medicine, and is particularly characterized in two aspects, and firstly, the preparation method can generate more impurities. As in patent CN113072502a, the following impurities are produced during the synthesis of edaravone by reaction of phenylhydrazine with ethyl acetoacetate:
In addition, phenylhydrazine as a starting material belongs to genotoxic impurities, and edaravone prepared by the method is used as a brain protecting agent and the preparation of the medicine is used as an injection, so that the residue of the genotoxic impurities is strictly controlled. The residual phenylhydrazine and byproduct phenylhydrazine derivatives in the edaravone product prepared by the method can still cause damage to human bodies even when the concentration is very low, can induce gene mutation and cause tumor generation, belongs to genotoxic substances, and needs to strictly control the content of the phenylhydrazine and byproduct phenylhydrazine derivatives in the product. At present, the edaravone prepared by the method can only control the residual phenylhydrazine and the byproduct phenylhydrazine derivative within the range meeting the quality requirement by continuously and repeatedly recrystallizing the edaravone, and the complete removal of the phenylhydrazine and the byproduct phenylhydrazine derivative cannot be realized only by continuous recrystallization. Therefore, the development of a new synthetic route for preparing edaravone has very important significance for improving the quality of edaravone medicines.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a synthetic method for preparing edaravone, which can avoid the use of phenylhydrazine as a genotoxic starting material.
According to research, halogenated benzene (compound formula I) and 3-methylpyrazole-5-ketone undergo a coupling reaction under the action of a copper reagent/alkali/additive to prepare edaravone, wherein the reaction formula is as follows:
the copper reagent used in the reaction is selected from Cu 2O,CuI,Cu(acac)2,Cu(OAc)2.
The base used in the reaction is selected from K 3PO4,t BuOK.
The additives used in the reaction are selected from the group consisting of oxalyl diamine compounds, including N 1,N2 -bis (thiophen-2-ylmethyl) oxalyl diamine, N 1,N2 -bis (2, 4, 6-trimethoxyphenyl) oxalyl diamine, N 1,N2 -bis (2-phenyl-4-methylphenyl) oxalyl diamine, N 1 - (1-naphthyl) -N 2 -alkyl-type oxalyl diamine, N 1 -benzyl-N 2 - (5-methyl- [1,1' -biphenyl ] -2-yl) oxalyl diamine, N 1,N2 -bis (phenylethyl) oxalyl diamine, N 1,N2 -bis ([ 1,1' -biphenyl ] -2-diyl) oxalyl diamine, N 1 -benzyl-N 2 - ([ 1,1' -biphenyl ] -2-yl) oxalyl diamine, N 1,N2 -bis (naphthalene-1-ylmethyl) oxalyl diamine, N 1,N2 -bis (3-methylthio-2-ylmethyl) oxalyl diamine, N 1,N2 -bis (furan-2-ylmethyl) oxalyl diamine.
The solvent used in the reaction is tert-butanol, 1, 4-dioxane, DMSO, DMF.
X in the formula I is Br, I and Cl.
The reaction operation is simple, the used reagent has no danger, the use of phenylhydrazine genotoxic compounds is avoided, and the method has important significance for quality control and quality improvement of the final product edaravone.
Detailed Description
The invention will be more particularly understood by the following examples, which are intended to illustrate, but not limit the scope of the invention.
Example one preparation of edaravone
The Schlenk flask was equipped with magnetic stirring and chlorobenzene (1.7 g,15.10 mmol), 3-methylpyrazol-5-one (1.0 g,10.19 mmol), cuprous oxide (220 mg,1.54 mmol), potassium phosphate (6.4 g,30.15 mmol) and N 1,N2 -bis (thiophen-2-ylmethyl) oxalamide (284 mg,1.02 mmol) were added sequentially under nitrogen. The system was replaced with nitrogen 3 times, and then t-butanol (8 mL) was added to the reaction system under nitrogen protection. After the addition was completed, the system was again replaced with nitrogen for 3 times, the Schlenk flask was closed, and the system was heated to 130±5 ℃ and reacted with rapid stirring for 24 hours. After the reaction was completed, the system was naturally cooled to room temperature, ethyl acetate (20 mL) was added and stirred for 5 minutes, filtration was performed, the organic solvent was removed from the filtrate under reduced pressure, and the residue was purified by ethyl acetate/heptane chromatography to give 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone, white solid, 1.44g, 81.1%).
Example two preparation of edaravone
The Schlenk flask was equipped with magnetic stirring and bromobenzene (3.5 g,22.29 mmol), 3-methylpyrazol-5 one (1.45 g,14.78 mmol), cuprous iodide (284 mg,1.50 mmol), potassium tert-butoxide (3.35 g,29.85 mmol) and N 1,N2 -bis (furan-2-ylmethyl) oxalyl diamine (370 mg,1.49 mmol) were added sequentially under nitrogen. The system was replaced 3 times with nitrogen, and DMSO (10 mL) was then added to the reaction system under nitrogen protection. After the addition was completed, the system was again replaced with nitrogen for 3 times, the Schlenk flask was closed, and the system was heated to 100±5 ℃ and reacted with rapid stirring for 18 hours. The system was cooled to room temperature naturally, ethyl acetate (25 mL) was added, stirred, filtered, the organic solvent was removed from the filtrate under reduced pressure, and the residue was purified by ethyl acetate/heptane chromatography to give 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone, white solid, 2.21g, 85.8%).
Example III preparation of edaravone
The Schlenk flask was equipped with magnetic stirring and iodobenzene (1.5 g,7.35 mmol), 3-methylpyrazol-5 one (600 mg,6.12 mmol), cuprous oxide (90 mg,0.63 mmol), potassium phosphate (3.1 g,14.60 mmol) and N 1,N2 -bis (thiophen-2-ylmethyl) oxalamide (175 mg,0.62 mmol) were added sequentially under nitrogen. The system was replaced with nitrogen 3 times, and then t-butanol (5 mL) was added to the reaction system under nitrogen protection. After the addition was completed, the system was again replaced with nitrogen for 3 times, the Schlenk flask was closed, and the system was heated to 75±5 ℃ and reacted with rapid stirring for 24 hours. The system was cooled to room temperature naturally, ethyl acetate (10 mL) was added, stirred, filtered, the organic solvent was removed from the filtrate under reduced pressure, and the residue was purified by ethyl acetate/heptane chromatography to give 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone, white solid, 800.5mg, 75.1%).
Claims (1)
1. A method for preparing edaravone, comprising the steps of: bromobenzene and 3-methylpyrazole-5-ketone undergo a coupling reaction under the action of a copper reagent/alkali/additive to prepare edaravone;
the specific reaction formula is as follows:
；
The copper reagent is CuI;
The alkali is t BuOK;
the additive is N 1,N2 bis (furan-2-ylmethyl) oxalyl diamine;
The solvent in the reaction is DMSO.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102180834A (en) * | 2011-03-24 | 2011-09-14 | 江苏正大丰海制药有限公司 | Preparation method for edaravone |
| CN113929626A (en) * | 2020-07-13 | 2022-01-14 | 苏州特瑞药业有限公司 | Method for synthesizing eltrombopag |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102180834A (en) * | 2011-03-24 | 2011-09-14 | 江苏正大丰海制药有限公司 | Preparation method for edaravone |
| CN113929626A (en) * | 2020-07-13 | 2022-01-14 | 苏州特瑞药业有限公司 | Method for synthesizing eltrombopag |
Non-Patent Citations (1)
| Title |
|---|
| "Regioselective Synthesis of Heteroaryl Triflones by LDA (Lithium Diisopropylamide)-Mediated Anionic Thia-Fries Rearrangement";Xiu-Hua Xu等;Org. Lett.;第14卷(第10期);2544-2547 * |
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Address after: 226123 No.18, Qinghua Road, Sanchang street, Haimen District, Nantong City, Jiangsu Province Applicant after: Jiangsu Huiju Pharmaceutical Co.,Ltd. Address before: 226123 No.18, Qinghua Road, Sanchang street, Haimen District, Nantong City, Jiangsu Province Applicant before: Jiangsu Huiju Pharmaceutical Co.,Ltd. |
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