CN111747926B - Improved synthetic process method of topiramate free base - Google Patents
Improved synthetic process method of topiramate free base Download PDFInfo
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- CN111747926B CN111747926B CN202010579558.5A CN202010579558A CN111747926B CN 111747926 B CN111747926 B CN 111747926B CN 202010579558 A CN202010579558 A CN 202010579558A CN 111747926 B CN111747926 B CN 111747926B
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- inorganic base
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- epoxy compound
- free base
- topiramate
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- 239000012458 free base Substances 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 title claims description 23
- KJADKKWYZYXHBB-XBWDGYHZSA-N Topiramic acid Chemical compound C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)O[C@H]2[C@@H]2OC(C)(C)O[C@@H]21 KJADKKWYZYXHBB-XBWDGYHZSA-N 0.000 title claims description 16
- 229960004394 topiramate Drugs 0.000 title claims description 16
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000004593 Epoxy Substances 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 13
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 230000035484 reaction time Effects 0.000 claims abstract description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 38
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical group OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000003513 alkali Substances 0.000 description 7
- UPZBLXREZJIOHJ-UHFFFAOYSA-N 1-hydroxy-2-piperidinone Chemical compound ON1CCCCC1=O UPZBLXREZJIOHJ-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- OXILSFMNCPZGAH-UHFFFAOYSA-N 1-[(1-benzyl-4-hydroxypiperidin-4-yl)methyl]pyridin-2-one hydrochloride Chemical compound Cl.C1CN(CC=2C=CC=CC=2)CCC1(O)CN1C=CC=CC1=O OXILSFMNCPZGAH-UHFFFAOYSA-N 0.000 description 1
- LCEMZRIFGNFQHW-UHFFFAOYSA-N 1-hydroxypiperidin-2-one hydrochloride Chemical compound Cl.ON1C(CCCC1)=O LCEMZRIFGNFQHW-UHFFFAOYSA-N 0.000 description 1
- JMRYYMBDXNZQMH-UHFFFAOYSA-N 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)butan-1-one;hydrochloride Chemical compound Cl.C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 JMRYYMBDXNZQMH-UHFFFAOYSA-N 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 0.000 description 1
- UUZYBYIOAZTMGC-UHFFFAOYSA-M benzyl(trimethyl)azanium;bromide Chemical compound [Br-].C[N+](C)(C)CC1=CC=CC=C1 UUZYBYIOAZTMGC-UHFFFAOYSA-M 0.000 description 1
- KXHPPCXNWTUNSB-UHFFFAOYSA-M benzyl(trimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC1=CC=CC=C1 KXHPPCXNWTUNSB-UHFFFAOYSA-M 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 230000007278 cognition impairment Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- AEDZKIACDBYJLQ-UHFFFAOYSA-N ethane-1,2-diol;hydrate Chemical compound O.OCCO AEDZKIACDBYJLQ-UHFFFAOYSA-N 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- -1 hydroxypiperidone compound Chemical class 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The invention provides a preparation method for improving the conversion rate of an improved free base of the eperidone, which comprises the step of reacting 2-hydroxypyridine with an epoxy compound shown in a formula I in an organic solvent under the action of a phase transfer catalyst and an inorganic base to obtain the free base of the eperidone shown in a formula II. The preparation provided by the invention greatly improves the reaction efficiency, reduces the reaction time, improves the reaction yield and is very suitable for industrial production.
Description
Technical Field
The invention particularly relates to the field of medicines, and relates to an improved method for synthesizing a free base of eperidone.
Technical Field
Hydroxypiperidone hydrochloride, english name (Hydione Hydrochloride), chemical name 1- [ (1-benzyl-4-hydroxypiperidin-4-yl) -methyl ] -pyridin-2 (1H) -one hydrochloride. The structural formula of the haloperidol hydrochloride is shown as follows:
the compound is a double-target antidepressant drug independently developed by the national institute of military medical science and research, and can be used for preventing or treating central nervous system diseases related to 5-HT system dysfunction, including depression, mania, cognitive deficit, schizophrenia, pain and the like.
Patent CN102241667a discloses a hydroxypiperidone compound and a preparation method thereof:
the method comprises the following steps: ethylene glycol monomethyl ether and water are used as reaction solvents, 2-aminopyridine and epoxy shown in a formula I are used as raw materials, the raw materials react for 3 days, ethanol and fumaric acid are added for dissolution, then cooling is performed, diethyl ether is added, an organic phase is distilled to dry the solvents, sodium hydroxide and sodium acetate are added for alkalization, dichloromethane extraction is performed, and the hydroxypiperidone free alkali shown in a formula II is obtained through column chromatography.
The ethylene glycol monomethyl ether adopted by the process is used as a reaction solvent, the workshop production reaction time is long, the column chromatography process is complex, the control is difficult, the yield is too low, and the process is not suitable for workshop mass production.
The second method is as follows: DMF is used as a reaction solvent, 2-hydroxypyridine and epoxy are used as raw materials, the addition reaction is carried out for 1 day under the action of alkali, the washing is carried out by a potassium carbonate aqueous solution, after the solvent is evaporated, petroleum ether-ethyl acetate is added for crystallization, and the hydroxypiperidone free alkali is obtained by filtration.
The process has longer reaction time and lower process yield, and improves the synthetic process in view of the defects in the process.
Disclosure of Invention
The invention aims to provide an improved method for synthesizing a free base of topiramate.
Specifically, the invention provides a preparation method for improving the conversion rate of a free base of the hydroxypiperidone, which comprises the steps of reacting 2-hydroxypyridine and an epoxy compound shown in a formula I in an organic solvent under the action of a phase transfer catalyst and an inorganic base to obtain the free base of the hydroxypiperidone shown in a formula II, wherein the reaction formula is shown as follows:
in the preparation method of the topiramate free base, the phase transfer catalyst is selected from one or more of tetrabutylammonium bisulfate, tetrabutylammonium chloride, tetrabutylammonium bromide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltriethylammonium chloride and benzyltriethylammonium bromide.
In the preparation method of the topiramate free base, the molar ratio of the epoxy compound, the 2-hydroxypyridine and the inorganic base is 1:0.7 to 1.3:0.05 to 0.5, preferably 1:1.0 to 1.1:0.10 to 0.15.
In the above-mentioned process for preparing the free base of topiramate, the inorganic base is selected from potassium carbonate, sodium carbonate, lithium carbonate or cesium carbonate inorganic alkali aqueous solution or solid, preferably an inorganic alkali aqueous solution, and more preferably a potassium carbonate aqueous solution.
In the above process for the preparation of the free base of topiramate, the organic solvent is selected from the group consisting of: toluene or xylene, preferably toluene.
In the preparation method of the topiramate free base, the molar ratio of the epoxy compound to the phase transfer catalyst is 1:0.02 to 0.4, preferably 1:0.05 to 0.1.
In the preparation method of the topiramate free base, the volume ratio of the epoxy compound to the organic solvent is 1:3 to 12g/mL, preferably 1: 5-7 g/mL.
In the preparation method of the free base of the topiramate, the reaction temperature is 50-90 ℃, the reaction time is 6-24 h, and the reaction temperature is 55-65 ℃ and the reaction time is 8-10 h.
The preparation method of the free base of the topiramate provided by the invention has the innovation points that:
(1) The phase transfer catalyst is added, so that the reaction efficiency is greatly improved, the reaction time is reduced, the reaction yield is improved, and the method is very suitable for industrial production.
(2) The purity of the prepared hydroxy-pirtine free alkali is high, and the purity of the obtained hydroxy-pirtine hydrochloride can reach 99.8 percent after further salifying.
(3) In the prior art, DMF is used as a reaction solvent, so that a large amount of nitrogen-containing wastewater is discharged; the invention preferably uses toluene or xylene as a solvent, is easy to post-treat and recycle, and is more environment-friendly.
Detailed Description
The following specific examples of preparation are presented to illustrate the invention in more detail and are intended to be illustrative only and not limiting in any way.
Example 1
At room temperature, 20.3g of epoxy, 9.97g of 2-hydroxypyridine, 1.70g of tetrabutylammonium bisulfate and 102mL of toluene are weighed and mixed, then an aqueous solution with 1.38g of potassium carbonate is added, the temperature is raised to 55-65 ℃ for reaction for 8-10 h, 60mL of water is added for stirring, standing and layering, toluene phase is concentrated to dryness, 61mL of ethanol is added for heating and dissolving, then cooling to 0-10 ℃ is slowly carried out, filtration and drying are carried out, and white free base of the topiramate is obtained, the yield is 83.5%, and the purity is 97.1%.
Example 2
At room temperature, 20.3g of epoxy, 9.97g of 2-hydroxypyridine, 1.70g of tetrabutylammonium bisulfate and 102mL of toluene are weighed and mixed, then 1.38g of potassium carbonate solid is added, the temperature is raised to 55-65 ℃ for reaction for 8-10 h, 60mL of water is added for stirring, standing and layering are carried out, toluene phase is concentrated to dryness, 61mL of ethanol is added for heating and dissolving, then cooling to 0-10 ℃ is carried out slowly, filtration and drying are carried out, and white topiramate free base is obtained, the yield is 77.5%, and the purity is 96.8%.
Example 3
At room temperature, 20.3g of epoxy, 9.97g of 2-hydroxypyridine, 0.64g of tetrabutylammonium bromide and 61mL of dimethylbenzene are weighed and mixed, then an aqueous solution with 1.38g of potassium carbonate is added, the temperature is raised to 55-65 ℃ for reaction for 8-10 h under heat preservation, 60mL of water is added for stirring, standing and layering, toluene phase is concentrated to dryness, 21mL of ethanol is added for heating and dissolving, then the temperature is slowly lowered to 0-10 ℃ and the filtration is carried out, so that white hydroxypiperidone free base is obtained, the yield is 84.2%, and the purity is 96.5%.
Example 4
1.0kg of epoxy, 491.2g of 2-hydroxypyridine, 83.5g of tetrabutylammonium bisulfate and 5.0L of toluene are weighed and mixed at room temperature, then 68.0g of aqueous solution of potassium carbonate is added, the temperature is raised to 55-65 ℃ for reaction for 8-10 hours, 2.5L of water is added for stirring, standing and layering, the toluene phase is concentrated to dryness, 3.0L of ethanol is added for heating and clearing, then the temperature is slowly lowered to 0-10 ℃, filtering and drying are carried out, and white hydroxypiperidone free alkali is obtained, the yield is 84.3%, and the purity is 96.9%.
Example 5
At room temperature, 60.0kg of epoxy, 29.47kg of 2-hydroxypyridine, 5.01kg of tetrabutylammonium bisulfate and 300L of toluene are weighed and mixed, then an aqueous solution with 4.08kg of potassium carbonate is added, the temperature is raised to 55-65 ℃ for reaction for 8-10 h, 200L of water is added for stirring, standing and layering, toluene phase is concentrated to dryness, then 180L of ethanol is added for heating and dissolving, then cooling to 0-10 ℃ is slowly carried out, filtration and drying are carried out, and white free base of the topiramate is obtained, the yield is 84.3%, and the purity is 97.0%.
Claims (11)
1. The preparation method of the free base of the topiramate is characterized in that epoxy compound shown in a formula I and 2-hydroxypyridine react in an organic solvent under the action of a phase transfer catalyst and inorganic base to obtain the free base of the topiramate shown in a formula II, wherein the reaction formula is shown as follows:
the phase transfer catalyst is selected from tetrabutylammonium bisulfate, tetrabutylammonium chloride and tetrabutylammonium bromide;
the organic solvent is selected from toluene or xylene;
the inorganic base is selected from potassium carbonate, sodium carbonate, lithium carbonate or cesium carbonate.
2. The process of claim 1, wherein the inorganic base is selected from the group consisting of aqueous inorganic base solutions and inorganic base solids.
3. The preparation method according to claim 2, characterized in that the inorganic base is an aqueous inorganic base solution.
4. The preparation method according to claim 1, wherein the molar ratio of the epoxy compound, the 2-hydroxypyridine to the inorganic base is 1:0.7 to 1.3:0.05 to 0.5.
5. The method according to claim 4, wherein the molar ratio of the epoxy compound, the 2-hydroxypyridine to the inorganic base is 1:1.0 to 1.1:0.10 to 0.15.
6. The method of claim 1, wherein the molar ratio of the epoxy compound to the phase transfer catalyst is 1:0.02 to 0.4.
7. The method of claim 6, wherein the molar ratio of the epoxy compound to the phase transfer catalyst is 1:0.05 to 0.1.
8. The preparation method according to claim 1, wherein the volume ratio of the epoxy compound to the organic solvent is 1: 3-12 g/mL.
9. The method according to claim 8, wherein the volume ratio of the epoxy compound to the organic solvent is 1: 5-7 g/mL.
10. The preparation method according to claim 1, wherein the reaction temperature is 50-90 ℃ and the reaction time is 6-24 h.
11. The process according to claim 10, wherein the reaction temperature is 55 to 65 ℃ and the reaction time is 8 to 10 hours.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
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| CN202010579558.5A CN111747926B (en) | 2020-06-23 | 2020-06-23 | Improved synthetic process method of topiramate free base |
| PCT/CN2021/098608 WO2021259051A1 (en) | 2020-06-23 | 2021-06-07 | Method for improving synthesis process of hypidone free base |
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| CN202010579558.5A CN111747926B (en) | 2020-06-23 | 2020-06-23 | Improved synthetic process method of topiramate free base |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4563528A (en) * | 1984-04-19 | 1986-01-07 | Fabrica De Productos Quimicos Y Farmaceuticos Abello, S.A. | Process for preparing 5 pyridyl pyridine-2 (1H)-ones |
| WO2011140817A1 (en) * | 2010-05-14 | 2011-11-17 | 中国人民解放军军事医学科学院毒物药物研究所 | 1-[(4-hydroxypridin-4-yl) methyl] pyridine-2(1h)-one derivatives, preparation methods and uses thereof |
| CN109134432A (en) * | 2017-06-15 | 2019-01-04 | 泰州华元医药科技有限公司 | Deuterated antidepressant |
| CN110997656A (en) * | 2017-08-04 | 2020-04-10 | 百时美施贵宝公司 | Substituted indole compounds useful as inhibitors of TLR7/8/9 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101429168A (en) * | 2008-12-09 | 2009-05-13 | 江苏七洲绿色化工股份有限公司 | Method for preparation of bactericide of flutriafol |
| CN106588791A (en) * | 2016-11-01 | 2017-04-26 | 盐城辉煌化工有限公司 | Novel technology for synthesizing bactericide tebuconazole without solvent |
| CN111747926B (en) * | 2020-06-23 | 2024-01-30 | 浙江华海药业股份有限公司 | Improved synthetic process method of topiramate free base |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4563528A (en) * | 1984-04-19 | 1986-01-07 | Fabrica De Productos Quimicos Y Farmaceuticos Abello, S.A. | Process for preparing 5 pyridyl pyridine-2 (1H)-ones |
| WO2011140817A1 (en) * | 2010-05-14 | 2011-11-17 | 中国人民解放军军事医学科学院毒物药物研究所 | 1-[(4-hydroxypridin-4-yl) methyl] pyridine-2(1h)-one derivatives, preparation methods and uses thereof |
| CN109134432A (en) * | 2017-06-15 | 2019-01-04 | 泰州华元医药科技有限公司 | Deuterated antidepressant |
| CN110997656A (en) * | 2017-08-04 | 2020-04-10 | 百时美施贵宝公司 | Substituted indole compounds useful as inhibitors of TLR7/8/9 |
Non-Patent Citations (1)
| Title |
|---|
| Mohamed Abass.Substituted quinolinones. 21. Efficient N-alkylation of 4-chloro-6-methylquinolin-2(1H)-one under phase transfer catalysis conditions.2014,第10卷第362-368页. * |
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| WO2021259051A1 (en) | 2021-12-30 |
| CN111747926A (en) | 2020-10-09 |
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