CN105254603A - Synthetic technology of furan ammonium salt - Google Patents
Synthetic technology of furan ammonium salt Download PDFInfo
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- CN105254603A CN105254603A CN201510658259.XA CN201510658259A CN105254603A CN 105254603 A CN105254603 A CN 105254603A CN 201510658259 A CN201510658259 A CN 201510658259A CN 105254603 A CN105254603 A CN 105254603A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Furan Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
The invention belongs to the technical field of medical intermediate preparation, and particularly relates to a synthetic technology of furan ammonium salt. The synthetic technology comprises the steps that 2-acetyl furan is used as a raw material to form furanone acid through oxidative synthesis at first, then esterification is performed, the product reacts with methoxyamine to be synthesized into a methoxy group oximation product, the methoxy group oximation product is hydrolyzed and then reacts with an alcohol amine solvent, and the furan ammonium salt is obtained. Due to the fact that the furanone acid is esterified at first, the carbonyl activity is improved, and more oximation products are promoted to be converted into cis-form products. The content of the obtained anti-form furan ammonium salt is only 5-8%; compared with a traditional furan ammonium salt production method, the content of the anti-form furan ammonium salt is obviously reduced without lowering productivity.
Description
Technical field
The invention belongs to technical field of medical intermediate preparation, be specifically related to a kind of synthesis technique of SMIA.
Background technology
Cephalofruxin is a kind of non-semi-synthetic wide spectrum Cephalosporin class microbiotic through gastro-intestinal administration.SMIA is one of important intermediate of cephalofruxin.
Patent 200810121255.8 relate to the preparation method of SMIA, and the method is in reaction vessel, add 2-oxo-2-furyl acetic acid, water, and uses mineral acid adjust pH, then adds the Vasoxyl aqueous solution or its hydrochloride aqueous solution; Insulation reaction, control with mineral alkali and mineral acid in reaction process, reaction solution mineral acid adjust pH, then merges organic layer with organic solvent extraction; Organic layer passes into ammonia or liquefied ammonia, and filter centrifugation obtains crude product; Added by crude product in refining solvent, add activated carbon decolorizing, temperature rising reflux, filtered while hot removes gac, then mother liquor concentrations, cooling, crystallization are obtained product.This synthetic method reduces costs and reduces operation link, improves yield.But still yield is lower for the more existing technique of yield of 2-oxo-2-furyl acetic acid and Vasoxyl direct reaction.
Patent 200910097425.8 relate to the preparation method of SMIA, and the method is 1. reacted by Sodium Nitrite and acetic acid furans, generates furans ketone acid through oximate, rearrangement, hydrolysis; 2. two extraction furans ketone acid is extracted; 3. furans ketone acid generates 2-imino--2-furans acetic acid with the condensation of methoxy ammonium salt hydrochlorate again; 4. 2-imino--2-furans acetic acid is extracted; 5. then lead to ammonia salify, generate 2-methoxyimino-2-furans amine acetate; Wherein: the solvent that 2. step extracts the employing of furans ketone acid is butylacetate.The present invention is large 4 times of the dissolving loss ratio butylacetate of ethyl acetate in water at identical conditions, adopts butylacetate unit consumption can be declined 50% as solvent, reduce production cost.Further, present invention employs the temperature of reaction of the oximate of 58-60 DEG C, the production rate of furancarboxylic acid is less than 1%, substantially increases the yield of product, but the transformation efficiency of furans ketone acid is lower.
Summary of the invention
For the deficiencies in the prior art, the object of this invention is to provide a kind of synthesis technique of SMIA of applicable suitability for industrialized production, reduce trans SMIA, improve yield and the purity of product, reduce production cost.
The synthesis technique of SMIA of the present invention take 2-acetofuran as raw material, first oxidative synthesis furans ketone acid, then esterification, then with Vasoxyl Reactive Synthesis methoxyl group oximate product, through hydrolysis after react with alcohol ammonia solvent, obtain SMIA.
The synthesis technique of described SMIA, specifically comprises the steps:
(1) take 2-acetofuran as raw material, obtain furans ketone acid with oxidant reaction: be added drop-wise to by oxygenant in 2-acetofuran, dropwise, in reaction solution, add salt acid for adjusting pH to strongly-acid, obtain furanone acid solution;
(2) esterification under the effect of the vitriol oil of furans ketone acid and alcohol generates furanone acid esters: in furanone acid solution, add alcohol excess solution, and after adding the vitriol oil stirring reaction of catalytic amount, distillation removing volatile components, obtains furanone acid esters solution;
(3) furanone acid esters and Vasoxyl are obtained by reacting 2-methoxy imino-2-furans methyl acetate: in furans acetate solution, drip Vasoxyl solution regulate pH to acid, insulation 1.5-2.0h, obtains 2-methoxy imino-2-furans methyl acetate solution;
(4) 2-methoxy imino-2-furans methyl acetate alkaline hydrolysis: with basic solution, 2-methoxy imino-2-furans methyl acetate solution ph is adjusted to 10.0-11.0 at 25 DEG C, insulated and stirred 3.5-4.5h, with salt acid for adjusting pH to 6.5-7.5, with organic solvent extraction, obtain 2-methoxy imino-2-furans acetic acid solution;
(5) 2-methoxy imino-2-furans acetic acid solution and alcohol ammonia solvent react: it is 8.0-9.0 that 2-methoxy imino-2-furans acetic acid solution is dripped ammonia ethanol solution to pH value under ice-water bath condition, dropwise, continue to stir 0.5-1.5h, filter to obtain SMIA.
Wherein, preferred technical scheme is as follows:
In step (1), temperature of reaction is 25-80 DEG C.
In step (1), the mol ratio of oxygenant and 2-acetofuran is 1.2-2.0:1.0, is preferably 1.3:1.0.
In step (1), oxygenant is preferably Sodium Nitrite.
In step (2), the mass ratio of alcohol and furans ketone acid is 1.5-2.0:1.0, is preferably 1.5:1.0.
In step (3), pH value is 2.0-6.0, is preferably 3.5; Holding temperature is 0-40 DEG C.
The synthesis technique of described SMIA, when adopting methyl alcohol to carry out step of esterification, correlated response formula is as follows:
In sum, beneficial effect of the present invention is as follows:
(1) the present invention take 2-acetofuran as raw material, oxidative synthesis furans ketone acid, then esterification, then reacts with Vasoxyl, and synthesizing methoxy oximate product, is then hydrolyzed, and is obtained by reacting SMIA with alcohol ammonia solvent.By first for furans ketone acid esterification, improve the activity of carbonyl, impel oximated product to be more converted into cis-product.The content of the trans SMIA prepared is only 5%-8%, and compared with traditional mode of production SMIA method, under the condition not reducing productive rate, the content of trans SMIA significantly reduces.
(2) technique of the present invention improves yield and the purity of product, reduces production cost.
Embodiment
Below in conjunction with embodiment, the present invention will be further described.
The all raw materials used in embodiment, except specified otherwise, are commercial.
Embodiment 1
(1) by 100mL water and 150g2-acetyl furan mix and blend, temperature controls at 30 DEG C, slow dropping sodium nitrite in aqueous solution (113g Sodium Nitrite and the mixing of 153mL water obtain), after dropwising, add concentrated hydrochloric acid (massfraction is 36%) adjust ph to 2.0, obtain furanone acid solution, Liquid Detection, transformation efficiency is 97.5%;
(2) in the furanone acid solution obtained, add 300g anhydrous methanol, and to control solution temperature be 35 DEG C, simultaneously to mixed solution and dripping 3 vitriol oils, 2.0h is reacted under stirring, after having reacted, distillation reaction liquid, remove excessive methyl alcohol, obtain furans ketone acid methyl esters;
(3) reduce the temperature to 20 DEG C, in the furans ketone acid methyl esters obtained, drip 110g Vasoxyl, regulate pH to 2.0, reaction 1.5h, Liquid Detection, the content of trans 2-methoxy imino-2-furans methyl acetate is 6%;
(4) to the mixed solution and dripping 60g sodium hydroxide solution that step (3) obtains, regulate pH to 11.0, after stirring reaction 3.5h, with salt acid for adjusting pH to 6.5, add 120mL methylene dichloride in solution, extract three times, collect organic phase, distillation removing methylene dichloride, obtains 2-methoxy imino-2-furans acetic acid;
(5) at 3 DEG C, in this solution, drip ammonia ethanol solution to pH=3.5, after keeping thermotonus 1.0h, through distillation, filter and obtain SMIA product 178.3g.
Embodiment 2
(1) by 200mL water and 306g2-acetyl furan mix and blend, temperature controls at 0 DEG C, slow dropping sodium nitrite in aqueous solution (282g Sodium Nitrite and the mixing of 312mL water obtain), after dropwising, adding concentrated hydrochloric acid (massfraction is 36%) adjust ph is 3.0, obtain furanone acid solution, Liquid Detection, transformation efficiency 98.7%;
(2) in the furanone acid solution obtained, add 650g dehydrated alcohol and temperature control solution temperature is 37 DEG C, simultaneously to mixed solution and dripping 3 vitriol oils, under stirring, react 1.2h, after having reacted, distillation reaction liquid, removes excessive ethanol, obtains furanone acetoacetic ester;
(3) reduce the temperature to 30 DEG C, in the furanone acetoacetic ester obtained, drip 230g Vasoxyl, regulate pH to 4.0, reaction 2.6h, Liquid Detection, the content of trans 2-methoxy imino-2-furans ethyl acetate is 6.5%;
(4) to the mixed solution and dripping 130g sodium hydroxide solution that step (3) obtains, regulate pH to 10.0, after stirring lower reaction 4.0h, with salt acid for adjusting pH to 7.0, add 140mL methylene dichloride in solution, extract three times, collect organic phase, distillation removing methylene dichloride, obtains 2-methoxy imino-2-furans acetic acid;
(5) at 0 DEG C, in this solution, drip ammonia ethanol solution to pH=5.5, after keeping thermotonus 1.0h, through distillation, filter and obtain SMIA product 365.8g.
Embodiment 3
(1) by 50mL water and 40g2-acetyl furan mix and blend, temperature controls at 78 DEG C, slow dropping sodium nitrite in aqueous solution (50g Sodium Nitrite and the mixing of 68mL water obtain), after dropwising, adding concentrated hydrochloric acid (massfraction is 36%) adjust ph is 2.0, obtain furanone acid solution, Liquid Detection, transformation efficiency 96.1%;
(2) in the furanone acid solution obtained, 90g anhydrous methanol is added and temperature control solution temperature is 32 DEG C, simultaneously to mixed solution and dripping 3 vitriol oils, react 5h under stirring, reacted rear distillation reaction liquid, remove excessive methyl alcohol, obtain furans ketone acid methyl esters;
(3) reduce the temperature to 30 DEG C, in the furans ketone acid methyl esters obtained, drip 48g Vasoxyl, regulate pH to 4.0, reaction 2.6h, Liquid Detection, the content of trans 2-methoxy imino-2-furans methyl acetate is 6.8%;
(4) to the mixed solution and dripping 28.2g sodium hydroxide solution that step (3) obtains, regulate pH to 11.0, after stirring lower reaction 4.5, with salt acid for adjusting pH to 7.0, add 80mL methylene dichloride in solution, extract three times, collect organic phase, distillation removing methylene dichloride, obtains 2-methoxy imino-2-furans acetic acid;
(5) at 0 DEG C, in this solution, drip ammonia ethanol solution to pH=5.5, after keeping thermotonus 1.0h, through distillation, filter and obtain SMIA product 59.8g.
Claims (7)
1. a synthesis technique for SMIA, is characterized in that: take 2-acetofuran as raw material, first oxidative synthesis furans ketone acid, then esterification, then with Vasoxyl Reactive Synthesis methoxyl group oximate product, through hydrolysis after react with alcohol ammonia solvent, obtain SMIA.
2. the synthesis technique of SMIA according to claim 1, is characterized in that: comprise the steps:
(1) take 2-acetofuran as raw material, obtain furans ketone acid with oxidant reaction: be added drop-wise to by oxygenant in 2-acetofuran, dropwise, in reaction solution, add salt acid for adjusting pH to strongly-acid, obtain furanone acid solution;
(2) esterification under the effect of the vitriol oil of furans ketone acid and alcohol generates furanone acid esters: in furanone acid solution, add alcohol excess solution, and after adding the vitriol oil stirring reaction of catalytic amount, distillation removing volatile components, obtains furanone acid esters solution;
(3) furanone acid esters and Vasoxyl are obtained by reacting 2-methoxy imino-2-furans methyl acetate: in furans acetate solution, drip Vasoxyl solution regulate pH to acid, insulation 1.5-2.0h, obtains 2-methoxy imino-2-furans methyl acetate solution;
(4) 2-methoxy imino-2-furans methyl acetate alkaline hydrolysis: with basic solution, 2-methoxy imino-2-furans methyl acetate solution ph is adjusted to 10.0-11.0 at 25 DEG C, insulated and stirred 3.5-4.5h, with salt acid for adjusting pH to 6.5-7.5, with organic solvent extraction, obtain 2-methoxy imino-2-furans acetic acid solution;
(5) 2-methoxy imino-2-furans acetic acid solution and alcohol ammonia solvent react: it is 8.0-9.0 that 2-methoxy imino-2-furans acetic acid solution is dripped ammonia ethanol solution to pH value under ice-water bath condition, dropwise, continue to stir 0.5-1.5h, filter to obtain SMIA.
3. the synthesis technique of SMIA according to claim 1, is characterized in that: in step (1), and temperature of reaction is 25-80 DEG C.
4. the synthesis technique of SMIA according to claim 1, is characterized in that: in step (1), and the mol ratio of oxygenant and 2-acetofuran is 1.2-2.0:1.0.
5. the synthesis technique of SMIA according to claim 1, is characterized in that: in step (1), and oxygenant is Sodium Nitrite.
6. the synthesis technique of SMIA according to claim 1, is characterized in that: in step (2), and the mass ratio of alcohol and furans ketone acid is 1.5-2.0:1.0.
7. the synthesis technique of SMIA according to claim 1, is characterized in that: in step (3), and pH value is 2.0-6.0, and holding temperature is 0-40 DEG C.
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Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106187960A (en) * | 2016-07-14 | 2016-12-07 | 四平市精细化学品有限公司 | A kind of preparation method of 2 methoxyimino 2 furyl acetic acid ammonium salts |
| CN107011299A (en) * | 2017-03-24 | 2017-08-04 | 四平市精细化学品有限公司 | A kind of method that SMIA is reclaimed in the waste liquid from SMIA |
| CN107573305A (en) * | 2017-08-30 | 2018-01-12 | 成都化润药业有限公司 | A kind of preparation method of SMIA |
| CN107892678A (en) * | 2017-12-06 | 2018-04-10 | 成都化润药业有限公司 | The SMIA preparation technology of recyclable furans ketone acid |
| CN110003043A (en) * | 2019-04-28 | 2019-07-12 | 山东金城医药化工有限公司 | The method of methoxamine is recycled from furan ammonium salt waste water |
| CN110590719A (en) * | 2019-08-15 | 2019-12-20 | 安徽金禾实业股份有限公司 | Green method for preparing 2-furoic acid |
| CN112300102A (en) * | 2020-10-27 | 2021-02-02 | 山东鑫泉医药有限公司 | Synthetic method of furan ammonium salt |
| CN112979592A (en) * | 2021-03-01 | 2021-06-18 | 安徽金轩科技有限公司 | Improved process for refining and crystallizing furan ammonium salt |
| CN113372363A (en) * | 2021-04-15 | 2021-09-10 | 深圳市立国药物研究有限公司 | Preparation method of descarbamoyl cefuroxime |
| CN113999194A (en) * | 2021-11-22 | 2022-02-01 | 山东金城医药化工有限公司 | Process for the preparation of furan ammonium salts |
| CN114014823A (en) * | 2021-12-15 | 2022-02-08 | 山东金城医药化工有限公司 | Preparation method of trans-ethyl noraminothiazolyloximate |
| CN114133338A (en) * | 2021-11-17 | 2022-03-04 | 安徽金轩科技有限公司 | Device and method for recovering methoxyamine from oximation wastewater in production of furan ammonium salt |
| CN116178318A (en) * | 2023-03-06 | 2023-05-30 | 河南立诺制药有限公司 | Synthesis method of furan ammonium salt |
| CN116355974A (en) * | 2023-03-22 | 2023-06-30 | 山东金城医药研究院有限公司 | Production process for synthesizing furan ammonium salt by enzyme-chemical method |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102863407A (en) * | 2012-10-10 | 2013-01-09 | 山东金城医药化工股份有限公司 | Preparation method of 2-methoxyiminofurylacetic acid amonium salt |
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- 2015-10-12 CN CN201510658259.XA patent/CN105254603B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102863407A (en) * | 2012-10-10 | 2013-01-09 | 山东金城医药化工股份有限公司 | Preparation method of 2-methoxyiminofurylacetic acid amonium salt |
Cited By (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106187960A (en) * | 2016-07-14 | 2016-12-07 | 四平市精细化学品有限公司 | A kind of preparation method of 2 methoxyimino 2 furyl acetic acid ammonium salts |
| CN107011299A (en) * | 2017-03-24 | 2017-08-04 | 四平市精细化学品有限公司 | A kind of method that SMIA is reclaimed in the waste liquid from SMIA |
| CN107011299B (en) * | 2017-03-24 | 2019-05-31 | 四平市精细化学品有限公司 | A method of recycling furan ammonium salt from furan ammonium salt waste liquid |
| CN107573305A (en) * | 2017-08-30 | 2018-01-12 | 成都化润药业有限公司 | A kind of preparation method of SMIA |
| CN107892678A (en) * | 2017-12-06 | 2018-04-10 | 成都化润药业有限公司 | The SMIA preparation technology of recyclable furans ketone acid |
| CN110003043B (en) * | 2019-04-28 | 2021-12-14 | 山东金城医药化工有限公司 | Method for recovering methoxyamine from furan ammonium salt wastewater |
| CN110003043A (en) * | 2019-04-28 | 2019-07-12 | 山东金城医药化工有限公司 | The method of methoxamine is recycled from furan ammonium salt waste water |
| CN110590719A (en) * | 2019-08-15 | 2019-12-20 | 安徽金禾实业股份有限公司 | Green method for preparing 2-furoic acid |
| CN110590719B (en) * | 2019-08-15 | 2022-04-19 | 安徽金禾实业股份有限公司 | Green method for preparing 2-furoic acid |
| CN112300102A (en) * | 2020-10-27 | 2021-02-02 | 山东鑫泉医药有限公司 | Synthetic method of furan ammonium salt |
| CN112979592A (en) * | 2021-03-01 | 2021-06-18 | 安徽金轩科技有限公司 | Improved process for refining and crystallizing furan ammonium salt |
| CN113372363A (en) * | 2021-04-15 | 2021-09-10 | 深圳市立国药物研究有限公司 | Preparation method of descarbamoyl cefuroxime |
| CN114133338A (en) * | 2021-11-17 | 2022-03-04 | 安徽金轩科技有限公司 | Device and method for recovering methoxyamine from oximation wastewater in production of furan ammonium salt |
| CN113999194B (en) * | 2021-11-22 | 2023-09-12 | 山东金城医药化工有限公司 | Process for the preparation of furan ammonium salts |
| CN113999194A (en) * | 2021-11-22 | 2022-02-01 | 山东金城医药化工有限公司 | Process for the preparation of furan ammonium salts |
| CN114014823A (en) * | 2021-12-15 | 2022-02-08 | 山东金城医药化工有限公司 | Preparation method of trans-ethyl noraminothiazolyloximate |
| CN116178318A (en) * | 2023-03-06 | 2023-05-30 | 河南立诺制药有限公司 | Synthesis method of furan ammonium salt |
| CN116178318B (en) * | 2023-03-06 | 2024-05-07 | 河南立诺制药有限公司 | Synthesis method of furan ammonium salt |
| CN116355974A (en) * | 2023-03-22 | 2023-06-30 | 山东金城医药研究院有限公司 | Production process for synthesizing furan ammonium salt by enzyme-chemical method |
| CN116355974B (en) * | 2023-03-22 | 2023-08-18 | 山东金城医药研究院有限公司 | Production process for synthesizing furan ammonium salt by enzyme-chemical method |
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