CN114853666A - Purification method for preparing high-purity perampanel intermediate - Google Patents
Purification method for preparing high-purity perampanel intermediate Download PDFInfo
- Publication number
- CN114853666A CN114853666A CN202110146576.9A CN202110146576A CN114853666A CN 114853666 A CN114853666 A CN 114853666A CN 202110146576 A CN202110146576 A CN 202110146576A CN 114853666 A CN114853666 A CN 114853666A
- Authority
- CN
- China
- Prior art keywords
- petroleum ether
- perampanel
- dihydropyridin
- benzonitrile
- oxo
- 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.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 15
- PRMWGUBFXWROHD-UHFFFAOYSA-N perampanel Chemical compound O=C1C(C=2C(=CC=CC=2)C#N)=CC(C=2N=CC=CC=2)=CN1C1=CC=CC=C1 PRMWGUBFXWROHD-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 229960005198 perampanel Drugs 0.000 title claims abstract description 12
- 238000000746 purification Methods 0.000 title abstract description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 16
- DHSPRQBEGFHZBG-UHFFFAOYSA-N 2-(5-acetyl-2-oxo-1-phenylpyridin-3-yl)benzonitrile Chemical compound C(#N)C1=C(C=CC=C1)C=1C(N(C=C(C1)C(C)=O)C1=CC=CC=C1)=O DHSPRQBEGFHZBG-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003208 petroleum Substances 0.000 claims abstract description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000007670 refining Methods 0.000 claims abstract description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 239000012045 crude solution Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 2
- 238000009835 boiling Methods 0.000 claims 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 1
- 229960001701 chloroform Drugs 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- 238000004440 column chromatography Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000004108 freeze drying Methods 0.000 abstract 1
- 239000011259 mixed solution Substances 0.000 abstract 1
- 238000001953 recrystallisation Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 7
- 206010010904 Convulsion Diseases 0.000 description 6
- 238000001914 filtration Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 206010061334 Partial seizures Diseases 0.000 description 2
- 238000009098 adjuvant therapy Methods 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000003078 Generalized Epilepsy Diseases 0.000 description 1
- 208000028311 absence seizure Diseases 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000002566 clonic effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 201000007186 focal epilepsy Diseases 0.000 description 1
- 201000001993 idiopathic generalized epilepsy Diseases 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
Abstract
The invention relates to a refining method of a Perampanel intermediate, namely refining of 2- (5-acetyl-2-oxo-1-phenyl-1, 2-dihydropyridin-3-yl) benzonitrile. The method is characterized in that a mixed solution of ethyl acetate and petroleum ether is used for preparing a refined product by a recrystallization method. Compared with the traditional purification methods such as column chromatography, freeze-drying and the like, the method has the advantages of convenience, rapidness, suitability for industrial production and the like.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to a refining method of a perampanel intermediate.
Background
Perampanel was approved by the U.S. Food and Drug Administration (FDA) for marketing at 2012, 10 months and 22 days, and is suitable for adjuvant treatment of epilepsy. At present, in patients over 55 countries (including australia, north america, europe, asia and russia) who are 12 years old or older, pirampanel has been approved as an adjunct treatment for focal epilepsy with or without secondary generalized epilepsy. In north america, europe, asia and russia, pirampanel is also approved as an adjuvant therapy for Primary Generalized Tonic Clonic (PGTC) seizures in patients over 12 years of age. Studies and clinical evidence in preclinical models of epilepsy suggest that perampanel has potential for antiepileptic activity and is well tolerated and effective with or without secondary generalization, primary generalized seizures and other focal seizures. Furthermore, the use of perampanel in patients in the real world has extensive clinical experience. Notably, pirampanel has not been shown to exacerbate other types of seizures, such as absence or myoclonic seizures.
Perampanel can be synthesized from 2- (5-acetyl-2-oxo-1-phenyl-1, 2-dihydropyridin-3-yl) benzonitrile in one step, but the preparation of 2- (5-acetyl-2-oxo-1-phenyl-1, 2-dihydropyridin-3-yl) benzonitrile usually requires the use of solvents such as DMF and the like, and by-products exist in the reaction, so the purification method for preparing the high-purity Perampanel intermediate is of great significance.
Perampanel can be synthesized in one step from 2- (5-acetyl-2-oxo-1-phenyl-1, 2-dihydropyridin-3-yl) benzonitrile according to patent CN103980188BCN, which has the following reaction formula:
according to patent CN103980188B — CN, 2- (5-acetyl-2-oxo-1-phenyl-1, 2-dihydropyridin-3-yl) benzonitrile is prepared, which has the following reaction formula:
because the preparation of 2- (5-acetyl-2-oxo-1-phenyl-1, 2-dihydropyridin-3-yl) benzonitrile intermediate is expensive and the number of synthesis steps is large, the search for a reaction condition for efficiently purifying a crude solution of 2- (5-acetyl-2-oxo-1-phenyl-1, 2-dihydropyridin-3-yl) benzonitrile is crucial for industrial production. Currently, the method used according to patent CN103980188B — CN is a purification using heptane or column chromatography, but the cost is relatively high.
In view of the above, the inventor has conducted a great deal of experimental research and found that the ethyl acetate-petroleum ether-crude solution system has a good purification effect on 2- (5-acetyl-2-oxo-1-phenyl-1, 2-dihydropyridin-3-yl) benzonitrile.
Disclosure of Invention
The invention relates to a method for refining a Perampanel intermediate, which is characterized by comprising the following steps: the newly prepared crude solution of 2- (5-acetyl-2-oxo-1-phenyl-1, 2-dihydropyridin-3-yl) benzonitrile is used in a ratio of 10: 15: stirring the mixed solvent of the ethyl acetate and the petroleum ether uniformly, heating and refluxing to be clear, cooling, stirring and crystallizing, controlling the temperature to be 20-25 ℃, and filtering and drying after crystallization to obtain a refined product.
Detailed Description
The invention is further illustrated, but is not to be construed as being limited by the following examples
Example 1:
50ml of the freshly prepared crude DMF solution of 2- (5-acetyl-2-oxo-1-phenyl-1, 2-dihydropyridin-3-yl) benzonitrile is added to 80ml of a solution prepared according to the ratio of 10: 15 ethyl acetate-petroleum ether solution, heating to 50 ℃ for 1 hour, filtering while the solution is hot, stirring for crystallization, controlling the temperature to be 20-25 ℃ for crystallization for 5 hours, and performing suction filtration and drying to obtain a refined product with the chemical purity of 99.1 percent and the maximum single impurity content of 0.06 percent.
Example 2:
adding 10ml of the newly prepared crude DMF solution of 2- (5-acetyl-2-oxo-1-phenyl-1, 2-dihydropyridin-3-yl) benzonitrile into 16ml of a mixture with the preparation ratio of 5:15 ethyl acetate-petroleum ether solution, heating to 50 ℃ for 1 hour, filtering while the solution is hot, stirring for crystallization, controlling the temperature to be 20-25 ℃ for crystallization for 5 hours, and performing suction filtration and drying to obtain a refined product with the chemical purity of 98.1 percent and the maximum single impurity content of 0.08 percent.
Claims (5)
2. Stirring the mixed solvent of ethyl acetate and petroleum ether uniformly, heating and refluxing to dissolve, cooling, stirring and crystallizing, controlling the temperature to be 20-25 ℃, and performing suction filtration and drying after crystallization to obtain a refined product.
3. A method according to claim 1, characterized in that: the solvent used for preparing the newly prepared 2- (5-acetyl-2-oxo-1-phenyl-1, 2-dihydropyridin-3-yl) benzonitrile is DMF, THF, DMA, trichloromethane, dioxane and other organic solvents.
4. A method according to claim 1, characterized in that: the adopted refining system is an ethyl acetate-petroleum ether mixed system, the boiling range specification of the petroleum ether is 30-60 ℃, 60-90 ℃ and 90-120 ℃, and the boiling range of the petroleum ether is preferably 60-90 ℃.
5. A method according to claim 3, characterized in that: the system ratio of ethyl acetate-petroleum ether-crude solution is 5: 15: 1 to 10: 15: 1.
Priority Applications (1)
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CN202110146576.9A CN114853666A (en) | 2021-02-03 | 2021-02-03 | Purification method for preparing high-purity perampanel intermediate |
Applications Claiming Priority (1)
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CN202110146576.9A CN114853666A (en) | 2021-02-03 | 2021-02-03 | Purification method for preparing high-purity perampanel intermediate |
Publications (1)
Publication Number | Publication Date |
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CN114853666A true CN114853666A (en) | 2022-08-05 |
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CN202110146576.9A Pending CN114853666A (en) | 2021-02-03 | 2021-02-03 | Purification method for preparing high-purity perampanel intermediate |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116396212A (en) * | 2023-06-09 | 2023-07-07 | 天津辰欣药物研究有限公司 | Preparation method of high-purity pirenzenenaphthalene intermediate |
-
2021
- 2021-02-03 CN CN202110146576.9A patent/CN114853666A/en active Pending
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116396212A (en) * | 2023-06-09 | 2023-07-07 | 天津辰欣药物研究有限公司 | Preparation method of high-purity pirenzenenaphthalene intermediate |
CN116396212B (en) * | 2023-06-09 | 2023-09-01 | 天津辰欣药物研究有限公司 | Preparation method of high-purity pirenzenenaphthalene intermediate |
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