CN111747926A - Improved method for synthesis process of free hydroxypiperone alkali - Google Patents
Improved method for synthesis process of free hydroxypiperone alkali Download PDFInfo
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- CN111747926A CN111747926A CN202010579558.5A CN202010579558A CN111747926A CN 111747926 A CN111747926 A CN 111747926A CN 202010579558 A CN202010579558 A CN 202010579558A CN 111747926 A CN111747926 A CN 111747926A
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- inorganic base
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- 238000000034 method Methods 0.000 title claims description 26
- 239000003513 alkali Substances 0.000 title description 14
- 230000015572 biosynthetic process Effects 0.000 title description 4
- 238000003786 synthesis reaction Methods 0.000 title description 4
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 12
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 8
- 230000035484 reaction time Effects 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 41
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- 239000004593 Epoxy Substances 0.000 claims description 13
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 6
- 239000012458 free base Substances 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 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
- 239000008096 xylene Substances 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
- CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 0.000 claims description 2
- UUZYBYIOAZTMGC-UHFFFAOYSA-M benzyl(trimethyl)azanium;bromide Chemical compound [Br-].C[N+](C)(C)CC1=CC=CC=C1 UUZYBYIOAZTMGC-UHFFFAOYSA-M 0.000 claims description 2
- KXHPPCXNWTUNSB-UHFFFAOYSA-M benzyl(trimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC1=CC=CC=C1 KXHPPCXNWTUNSB-UHFFFAOYSA-M 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
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 150000002118 epoxides Chemical class 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- UPZBLXREZJIOHJ-UHFFFAOYSA-N 1-hydroxy-2-piperidinone Chemical compound ON1CCCCC1=O UPZBLXREZJIOHJ-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 7
- 238000001816 cooling Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 238000004321 preservation Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- 239000007810 chemical reaction solvent Substances 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
- 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000002904 solvent Substances 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
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-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
- 208000015114 central nervous system disease Diseases 0.000 description 1
- -1 cesium carbonate inorganic bases Chemical class 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000001149 cognitive effect 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
- 230000007812 deficiency Effects 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
- 238000001704 evaporation Methods 0.000 description 1
- 235000011087 fumaric acid Nutrition 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
- 231100000614 poison Toxicity 0.000 description 1
- 238000011084 recovery 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
- 230000002194 synthesizing effect Effects 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
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
- Catalysts (AREA)
Abstract
The invention provides a preparation method for improving the conversion rate of free hydroxypeppirone, which comprises the step of reacting 2-hydroxypyridine with an epoxide shown as a formula I in an organic solvent under the action of a phase transfer catalyst and an inorganic base to obtain the free hydroxypeppirone shown as 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 relates to the field of medicines, in particular to an improved method for a synthesis process of free hydroxypiperidone alkali.
Technical Field
Hydroxypiperidone Hydrochloride, the english name (hydroclone), has the chemical name 1- [ (1-benzyl-4-hydroxypiperidin-4-yl) -methyl ] -pyridin-2 (1H) -one Hydrochloride. The structural formula of the hydroxypiperone hydrochloride is shown as follows:
the compound is a double-target antidepressant drug independently developed by the institute of poison drugs of the military medical academy of sciences of Chinese people liberation force, and can be used for preventing or treating central nervous system diseases related to 5-HT system dysfunction, including depression, mania, cognitive deficiency, schizophrenia, pain and the like.
Patent CN102241667A discloses an oxypeperisone compound and a preparation method thereof:
the method comprises the following steps: using ethylene glycol monomethyl ether and water as reaction solvents, using 2-aminopyridine and an epoxy compound shown in formula I as raw materials, reacting for 3 days, adding ethanol and trans-butenedioic acid for dissolving, cooling, adding diethyl ether, evaporating an organic phase to dryness, adding sodium hydroxide and sodium acetate for alkalization, extracting by dichloromethane, and carrying out column chromatography to obtain the free hydroxypiperidone alkali shown in formula II.
The ethylene glycol monomethyl ether adopted by the process is used as a reaction solvent, the reaction time of workshop production is long, the column chromatography procedure is complex and is not easy to control, and the yield is too low, so that the process is not suitable for large-scale workshop production.
The second method comprises the following steps: DMF is taken as a reaction solvent, 2-hydroxypyridine and epoxy are taken as raw materials, addition reaction is carried out for 1 day under the action of alkali, potassium carbonate aqueous solution is washed, the solvent is evaporated to dryness, then petroleum ether-ethyl acetate is added for crystallization, and finally the free hydroxypiperone alkali is obtained by filtration.
The process has longer reaction time and lower process yield, and the synthesis process is improved in view of the defects in the process.
Disclosure of Invention
The invention aims to provide an improved method for synthesizing free base of oxyphenirazone.
Specifically, the invention provides a preparation method for improving the conversion rate of free hydroxypeppirone base, which comprises the following steps of reacting 2-hydroxypyridine and an epoxide 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 hydroxypeppirone base shown in a formula II, wherein the reaction formula is as follows:
in the above process for preparing free hydroxypiperidone base, the phase transfer catalyst is one or more selected from tetrabutylammonium hydrogen sulfate, tetrabutylammonium chloride, tetrabutylammonium bromide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltriethylammonium chloride and benzyltriethylammonium bromide.
In the above process for preparing free hydroxypiperidone base, the molar ratio of epoxy compound, 2-hydroxypyridine and inorganic base is 1: 0.7-1.3: 0.05-0.5, preferably 1: 1.0-1.1: 0.10 to 0.15.
In the above process for preparing free hydroxypiperone base, the inorganic base is selected from aqueous solutions or solids of potassium carbonate, sodium carbonate, lithium carbonate or cesium carbonate inorganic bases, preferably aqueous solutions of inorganic bases, and more preferably aqueous solutions of potassium carbonate.
In the above process for the preparation of free base of hydroxypiperidone, the organic solvent is selected from the group consisting of: toluene or xylene, preferably toluene.
In the above process for preparing free base of hydroxypiperidone, the molar ratio of epoxide to phase transfer catalyst is 1: 0.02 to 0.4, preferably 1: 0.05 to 0.1.
In the above process for preparing free base of hydroxypiperidone, the volume ratio of epoxy compound to organic solvent is 1: 3-12 g/mL, preferably 1: 5-7 g/mL.
In the preparation method of the free hydroxypiperidone alkali, the reaction temperature is 50-90 ℃, the reaction time is 6-24 hours, the reaction temperature is further preferably 55-65 ℃, and the reaction time is 8-10 hours.
The preparation method of free hydroxypiperidone alkali provided by the invention has the following innovation points:
(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 free hydroxypeppirone alkali obtained by the method has high purity, and the purity of the obtained hydroxypeppirone hydrochloride can reach 99.8% after further salification.
(3) In the prior art, DMF is used as a reaction solvent, which brings about the discharge of a large amount of nitrogen-containing wastewater; the invention preferably uses toluene or xylene as solvent, is easy for post-treatment and recovery, and is more environment-friendly.
Detailed Description
The following specific preparation examples are intended to illustrate the invention in detail, and the examples are intended to be illustrative in more detail only, and not to limit the invention in any way.
Example 1
Weighing 20.3g of epoxy, 9.97g of 2-hydroxypyridine, 1.70g of tetrabutylammonium hydrogen sulfate and 102mL of toluene at room temperature, mixing, adding an aqueous solution in which 1.38g of potassium carbonate is dissolved, heating to 55-65 ℃, carrying out heat preservation reaction for 8-10 h, adding 60mL of water, stirring, standing for layering, concentrating a toluene phase to dryness, adding 61mL of ethanol, heating to dissolve, slowly cooling to 0-10 ℃, filtering, and drying to obtain white hydroxypiprepin free alkali, wherein the yield is 83.5% and the purity is 97.1%.
Example 2
Weighing 20.3g of epoxy, 9.97g of 2-hydroxypyridine, 1.70g of tetrabutylammonium hydrogen sulfate and 102mL of toluene at room temperature, mixing, adding 1.38g of potassium carbonate solid, heating to 55-65 ℃, carrying out heat preservation reaction for 8-10 h, adding 60mL of water, stirring, standing for layering, concentrating a toluene phase to dryness, adding 61mL of ethanol, heating to dissolve, slowly cooling to 0-10 ℃, filtering, and drying to obtain white hydroxypiperidone free alkali, wherein the yield is 77.5%, and the purity is 96.8%.
Example 3
Weighing 20.3g of epoxy, 9.97g of 2-hydroxypyridine, 0.64g of tetrabutylammonium bromide and 61mL of xylene at room temperature, mixing, adding an aqueous solution dissolved with 1.38g of potassium carbonate, heating to 55-65 ℃, carrying out heat preservation reaction for 8-10 h, adding 60mL of water, stirring, standing for layering, concentrating a toluene phase to dryness, adding 21mL of ethanol, heating to dissolve, cleaning, slowly cooling to 0-10 ℃, and filtering to obtain white hydroxypiperidone free alkali, wherein the yield is 84.2% and the purity is 96.5%.
Example 4
Weighing 1.0kg of epoxy, 491.2g of 2-hydroxypyridine, 83.5g of tetrabutylammonium hydrogen sulfate and 5.0L of toluene at room temperature, mixing, adding an aqueous solution in which 68.0g of potassium carbonate is dissolved, heating to 55-65 ℃, carrying out heat preservation reaction for 8-10 h, adding 2.5L of water, stirring, standing for layering, concentrating a toluene phase to dryness, adding 3.0L of ethanol, heating to dissolve, slowly cooling to 0-10 ℃, filtering, and drying to obtain white hydroxypiperidone free alkali, wherein the yield is 84.3%, and the purity is 96.9%.
Example 5
Weighing 60.0kg of epoxy, 29.47kg of 2-hydroxypyridine, 5.01kg of tetrabutylammonium hydrogen sulfate and 300L of toluene at room temperature, mixing, adding an aqueous solution in which 4.08kg of potassium carbonate is dissolved, heating to 55-65 ℃, carrying out heat preservation reaction for 8-10 h, adding 200L of water, stirring, standing for layering, concentrating a toluene phase to dryness, adding 180L of ethanol, heating to dissolve, slowly cooling to 0-10 ℃, filtering, and drying to obtain white hydroxypiprepin free alkali, wherein the yield is 84.3%, and the purity is 97.0%.
Claims (10)
1. A preparation method of free base of hydroxypeppirone is characterized in that epoxy compound shown in formula I and 2-hydroxypyridine are reacted in an organic solvent under the action of a phase transfer catalyst and an inorganic base to obtain the free base of hydroxypeppirone shown in formula II, wherein the reaction formula is as follows:
2. the method of claim 1, wherein the phase transfer catalyst is selected from one or more of tetrabutylammonium hydrogen sulfate, tetrabutylammonium chloride, tetrabutylammonium bromide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltriethylammonium chloride, and benzyltriethylammonium bromide.
3. The process according to claim 1, wherein the organic solvent is selected from toluene or xylene, preferably toluene.
4. The process according to claim 1, wherein the inorganic base is selected from an aqueous solution of an inorganic base or a solid of an inorganic base, preferably an aqueous solution of an inorganic base.
5. The method of claim 1, wherein the inorganic base is selected from potassium carbonate, sodium carbonate, lithium carbonate or cesium carbonate, preferably potassium carbonate.
6. The process of claim 1, wherein the molar ratio of epoxy, 2-hydroxypyridine and inorganic base is 1: 0.7-1.3: 0.05-0.5, preferably 1: 1.0-1.1: 0.10 to 0.15.
7. The method of claim 1, wherein the molar ratio of epoxy to phase transfer catalyst is 1: 0.02 to 0.4, preferably 1: 0.05 to 0.1.
8. The method of claim 1, wherein the ratio of the mass of epoxy to the volume of organic solvent is 1: 3-12 g/mL, preferably 1: 5-7 g/mL.
9. The preparation method according to claim 1, wherein the reaction temperature is 50 ℃ to 90 ℃ and the reaction time is 6 to 24 hours.
10. The preparation method according to claim 9, 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 |
|---|---|---|---|
| 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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| WO (1) | WO2021259051A1 (en) |
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|---|---|---|---|---|
| WO2021259051A1 (en) * | 2020-06-23 | 2021-12-30 | 浙江华海药业股份有限公司 | Method for improving synthesis process of hypidone free base |
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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2020
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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", vol. 10, pages 362 - 368 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021259051A1 (en) * | 2020-06-23 | 2021-12-30 | 浙江华海药业股份有限公司 | Method for improving synthesis process of hypidone free base |
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| WO2021259051A1 (en) | 2021-12-30 |
| CN111747926B (en) | 2024-01-30 |
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