CN1626506A - Preparing niclosamide in high purity and high yield - Google Patents
Preparing niclosamide in high purity and high yield Download PDFInfo
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- CN1626506A CN1626506A CN 200410059115 CN200410059115A CN1626506A CN 1626506 A CN1626506 A CN 1626506A CN 200410059115 CN200410059115 CN 200410059115 CN 200410059115 A CN200410059115 A CN 200410059115A CN 1626506 A CN1626506 A CN 1626506A
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- Prior art keywords
- niclosamide
- acid
- amine
- manufacture method
- described manufacture
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- RJMUSRYZPJIFPJ-UHFFFAOYSA-N niclosamide Chemical compound OC1=CC=C(Cl)C=C1C(=O)NC1=CC=C([N+]([O-])=O)C=C1Cl RJMUSRYZPJIFPJ-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 229960001920 niclosamide Drugs 0.000 title claims description 34
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- NKBASRXWGAGQDP-UHFFFAOYSA-N 5-chlorosalicylic acid Chemical compound OC(=O)C1=CC(Cl)=CC=C1O NKBASRXWGAGQDP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- -1 amine salt Chemical class 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 claims description 9
- 238000000967 suction filtration Methods 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 7
- 238000000746 purification Methods 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 claims description 5
- 238000005516 engineering process Methods 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 150000008431 aliphatic amides Chemical class 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 3
- 238000006386 neutralization reaction Methods 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- 229960004418 trolamine Drugs 0.000 claims description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims 1
- 238000007603 infrared drying Methods 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims 1
- 239000002798 polar solvent Substances 0.000 claims 1
- 238000010992 reflux Methods 0.000 claims 1
- 230000001105 regulatory effect Effects 0.000 claims 1
- 239000008096 xylene Substances 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 12
- 239000003513 alkali Substances 0.000 abstract 1
- VBEGHXKAFSLLGE-UHFFFAOYSA-N n-phenylnitramide Chemical compound [O-][N+](=O)NC1=CC=CC=C1 VBEGHXKAFSLLGE-UHFFFAOYSA-N 0.000 abstract 1
- 230000003472 neutralizing effect Effects 0.000 abstract 1
- 239000000843 powder Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 239000012452 mother liquor Substances 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000001476 alcoholic effect Effects 0.000 description 1
- 238000003763 carbonization Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012567 medical material Substances 0.000 description 1
- XIFJZJPMHNUGRA-UHFFFAOYSA-N n-methyl-4-nitroaniline Chemical compound CNC1=CC=C([N+]([O-])=O)C=C1 XIFJZJPMHNUGRA-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 201000004409 schistosomiasis Diseases 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000001577 simple distillation Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for preparing high-purity fenasal with high output rate includes reaction between 5-chlorosalicylic acid and nitrophenylamine to obtain raw fensal, and acid-alkali neutralizing.
Description
The present invention relates to a kind of method of the niclosamide active compound of purifying.
Niclosamide, its formal name used at school are 5-chloro-Whitfield's ointment-2 ' chloro-4 ' N-methyl-p-nitroaniline, English Niclosamide by name, the code name prevention and cure of schistosomiasis " 67 ", be WHO (WHO) approval be used to kill one of bilharzial main medicine.But by current technology 5-chloro-salicylic acid and the former medicine purity of ortho-chlor-para nitraniline synthetic low (56-70%), twice recrystallization post crystallization yield only reaches about 50%, and purity can only reach 94-96%, fails to satisfy the standard of medical material level medicine far away, simultaneously, industrial cost is high.
The niclosamide preparation method who the objective of the invention is to overcome the shortcoming of prior art and a kind of high purity, high yield are provided.It not only has simple to operate, steady quality but also cost is low and the characteristics of suitable suitability for industrialized production, and quality product reaches the Chinese Pharmacopoeia standard.Avoided repeatedly the complex operations of recrystallization purifying process, quality because of content in crude product fluctuation instability and the low defective workmanship of yield.
Niclosamide is because molecular weight is big, nitro and chlorine substituent are arranged on the phenyl ring, its solubleness in polarity and non-polar solvent is all very low, and the while is owing to its structure, character are similar to the raw material that synthesizes it, so general recrystallization method is difficult to reach requirement of high purity.Simultaneously because the fusing point lower (108 ℃) of ortho-chlor-para nitraniline, be lower than the temperature of building-up reactions, very easily carbonization and cause the generation of side reaction and cause the fluctuation of niclosamide crude product quality has increased the difficulty of Purification in reaction process.
Considering has phenolic hydroxyl group in the niclosamide molecule, has certain acidity, simultaneously the water-fast characteristic of niclosamide.The niclosamide crude product (content is at 54-85%) that the present invention has selected to be synthesized reacts the amine salt that generates niclosamide with organic amine, Clonitrilide after filtration, the neutralization, get pharmaceutical grade niclosamide (content 〉=99%) after the washing drying, and constant product quality, purification efficiency reaches more than 90%, is the suitability for industrialized production route an of the best.
Neutralization reaction of the present invention is to carry out in aqueous systems, has overcome the repeatedly complicated technology of recrystallization processing, has avoided the safety and environmental protection problem of the centrifuging under solvent condition.Because niclosamide is water insoluble, guaranteed that the yield of purifying reaches 90%, is far longer than the yield of recrystallizing technology.
Organic amine of the present invention only helps separating of niclosamide and reaction raw materials, does not consume in purification process, so can recycle.This invention simultaneously points out that the bigger organic amine of molecular weight is more conducive to the purification of niclosamide crude product, and the organic amine that molecular weight is bigger is difficult for loss in treating processes, so method of the present invention has the low characteristics of cost.
The organic amine that uses among the present invention can be aliphatic amide or aromatic hydrocarbons amine, especially with the aliphatic amide best results, as thanomin, diethanolamine, trolamine etc.When adopting aromatic hydrocarbons amine to carry out purification processes, should suitably improve temperature, temperature control is at 50-80 ℃.
The acid that adjusting PH uses can be hydrochloric acid, dilute sulphuric acid, rare nitric acid, dilute hydrobromic acid etc.
The present invention is because the solvent that uses is water-soluble good solvent, as ethanol, methyl alcohol, acetone, Virahol etc., and water, so the problem that does not exist dissolvent residual to exceed standard in the niclosamide product after purification.
Organic amine used in the present invention can be applied mechanically more than 7 batches, regulates mother liquor PH=10-12 with NaOH, is recyclable use through the simple distillation alcoholic solvent again.
Method of the present invention is simple, steady quality, yield height, cost are low, environmentally friendly, meets the Green Chemistry theme that chemical field is promoted the most.Simultaneously, further studies show that, when crude product niclosamide content reduces to 52.85%, still can disposablely obtain the niclosamide raw material of pharmaceutical grade, do not influence the quality and the yield of product by this technology.Experiment shows that this method do not have particular requirement to raw materials quality.
Below lift several concrete examples for your guidance:
Implement example 1: get synthetic gained sample (thick former powder of step, content between 54-85%, fluctuate all can) 15.0 grams, add ethanol 150-300ml, be heated with stirring to 40-60 ℃, the product section dissolving is glassy yellow suspension, slowly drip thanomin 4.8g, drip and finish, it is orange red that system gradually becomes, and continued back flow reaction 1 hour.Be cooled to room temperature then gradually, shelve anxious (-10 ℃ approximately, the 4-12 hour) suction filtration that spends the night that freezes in the chamber of refrigerator, get orange powdery solid 16.0 grams, (content=99.5%), yield reaches 88.7-93.1%.
Get step gained niclosamide organic amine salt powder 10 grams, after adding water 100ml and fully stirring, system is orange mashed prod, pH=8-9, and dropping dilute hydrochloric acid under stirring (1: 1, v/v) transfer pH=1, be heated to 60 ℃, constant temperature 15 minutes, system becomes faint yellow mashed prod, keeps reaction system pH=1, be cooled to 0 ℃ gradually, drain, get yellowish chromogen powder and mother liquor, filter cake 0 ℃ of water washing of 100ml 2 times, suction filtration, drying gets the pure product of pharmaceutical grade niclosamide (content is more than 99%), and two step total recoverys are greater than 90%.
Implement example 2: get synthetic gained sample (thick former powder of step, content between 54-85%, fluctuate all can) 15.0 grams, add ethanol 150-300ml, be heated with stirring to 56-58 ℃, the product section dissolving is glassy yellow suspension, slowly drip diethanolamine 8.5g, drip and finish, it is orange red that system gradually becomes, and continued back flow reaction 1 hour.Be cooled to room temperature then gradually, shelve anxious (-10 ℃ approximately, the 4-12 hour) suction filtration that spends the night that freezes in the chamber of refrigerator, get orange powdery solid 17.8 grams, (content=99.5%), yield reaches 88.7-93.1%.
Get step gained niclosamide organic amine salt powder 10 grams, after adding water 100ml and fully stirring, system is orange mashed prod pH=8-9, dropping dilute hydrochloric acid under at room temperature stirring (1: 1, v/v) transfer pH=1, system becomes faint yellow mashed prod, keep reaction system pH=1, be cooled to 0 ℃ gradually, drain, get yellowish chromogen powder and mother liquor, filter cake 100ml0 ℃ of water washing 2 times, suction filtration, drying, get the pure product of pharmaceutical grade niclosamide (content is more than 99%), total recovery is greater than 90%.
Implement example 3: get synthetic gained sample (thick former powder of step, content between 54-85%, fluctuate all can) 15.0 grams, add methyl alcohol 150-300ml, be heated with stirring to 40-60 ℃, the product section dissolving is glassy yellow suspension, slowly drip thanomin 4.8g, drip and finish, it is orange red that system gradually becomes, and continued back flow reaction 1 hour.Be cooled to room temperature then gradually, shelve anxious (-10 ℃ approximately, the 4-12 hour) suction filtration that spends the night that freezes in the chamber of refrigerator, the orange powdery solid, content is about 99.5%, yield reaches 88.7-93.1%.
Get step gained niclosamide organic amine salt powder 10 grams, after adding water 100ml and fully stirring, system is orange mashed prod, pH=8-9, and dropping dilute hydrochloric acid under stirring (1: 1, v/v) transfer pH=1, be heated to 60 ℃, constant temperature 15 minutes, system becomes faint yellow mashed prod, keeps reaction system pH=1, be cooled to 0 ℃ gradually, drain, get yellowish chromogen powder and mother liquor, filter cake 0 ℃ of water washing of 100ml 2 times, suction filtration, drying gets the pure product of pharmaceutical grade niclosamide (content is more than 99%), and two step total recoverys are greater than 90%.
Implement example 4: get synthetic gained sample (thick former powder of step, content between 54-85%, fluctuate all can) 15.0 grams, add acetone 150-300ml, be heated with stirring to 40-60 ℃, the product section dissolving is glassy yellow suspension, slowly drip thanomin 4.8g, drip and finish, it is orange red that system gradually becomes, and continued back flow reaction 1 hour.Be cooled to room temperature then gradually, shelve anxious (-10 ℃ approximately, the 4-12 hour) suction filtration that spends the night that freezes in the chamber of refrigerator, the orange powdery solid, content is about 99.5%, yield reaches 88.7-93.1%.
Get step gained niclosamide organic amine salt powder 10 grams, after adding water 100ml and fully stirring, system is orange mashed prod, pH=8-9, and dropping dilute hydrochloric acid under stirring (1: 1, v/v) transfer pH=1, be heated to 60 ℃, constant temperature 15 minutes, system becomes faint yellow mashed prod, keeps reaction system pH=1, be cooled to 0 ℃ gradually, drain, get yellowish chromogen powder and mother liquor, filter cake 0 ℃ of water washing of 100ml 2 times, suction filtration, drying gets the pure product of pharmaceutical grade niclosamide (content is more than 99%), and two step total recoverys are greater than 90%.
Claims (6)
1. preparation method of niclosamide crude product that purifies, it is characterized in that in organic solvent, niclosamide and organic amine being reacted the amine salt that makes niclosamide, then through acid-base neutralisation, suction filtration, the frozen water washing, one-time process is handled the niclosamide raw material (content 〉=98.5%) that can obtain pharmaceutical grade.Its organic amine is 1 with respect to the feed ratio of niclosamide: 1.2-1.6 (mol/mol); The infrared drying condition is 60-80 ℃, and be 5-8h time of drying; When regulating pH value with acid, control PH=1-3; Twice Tc 0-10 ℃, crystallization time 3-20h.
2. according to right 1 described manufacture method, the organic amine that uses can be aliphatic amide or aromatic hydrocarbons amine, especially with the aliphatic amide best results, and as thanomin, diethanolamine, trolamine, dimethylamine, Trimethylamine 99 etc.When adopting aromatic hydrocarbons amine to carry out purification processes, should suitably improve temperature, temperature control is at 50-80 ℃.
3. according to right 1 described manufacture method, the acid that adjusting PH uses can be hydrochloric acid, dilute sulphuric acid, rare nitric acid, dilute hydrobromic acid etc.
4. according to right 1 described manufacture method, the present invention is because the solvent that uses is water-soluble good polar solvent, as ethanol, methyl alcohol, acetone, Virahol etc. and water.
5. the raw material that niclosamide purifying technique provided by the invention adapts to is by 5-chloro-salicylic acid and ortho-chlor-para nitraniline by current technology, under phosphorus trichloride catalyzer condition, the refluxing xylene temperature condition is preparation down, and the former medicine purity of its synthetic can be low to moderate 56-70%.
6. according to right 1 described manufacture method, the content range of niclosamide crude product is 56-70%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410059115 CN1626506A (en) | 2004-08-10 | 2004-08-10 | Preparing niclosamide in high purity and high yield |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410059115 CN1626506A (en) | 2004-08-10 | 2004-08-10 | Preparing niclosamide in high purity and high yield |
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| CN1626506A true CN1626506A (en) | 2005-06-15 |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103183603A (en) * | 2011-12-30 | 2013-07-03 | 江苏天晟药业有限公司 | Crocetin organic amine salt and preparation method thereof |
| CN105017059A (en) * | 2015-07-02 | 2015-11-04 | 深圳市新阳唯康科技有限公司 | Novel crystal form of niclosamide and preparation method thereof |
| CN106496060A (en) * | 2016-10-21 | 2017-03-15 | 恒诚制药集团淮南有限公司 | A kind of preparation method of niclosamide ethanolamine salt |
| CN106748863A (en) * | 2016-11-14 | 2017-05-31 | 苏州市罗森助剂有限公司 | A kind of improvement preparation method of niclosamide ethanolamine salt |
| WO2021076922A1 (en) * | 2019-10-18 | 2021-04-22 | First Wave Bio, Inc. | Pharmaceutical formulations |
| US11564896B2 (en) | 2020-03-16 | 2023-01-31 | First Wave Bio, Inc. | Methods of treatment |
| US11793777B2 (en) | 2015-09-01 | 2023-10-24 | First Wave Bio, Inc. | Methods and compositions for treating conditions associated with an abnormal inflammatory response |
| WO2023249414A1 (en) * | 2022-06-22 | 2023-12-28 | 대웅바이오(주) | Method for producing benzoamine derivative |
-
2004
- 2004-08-10 CN CN 200410059115 patent/CN1626506A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103183603A (en) * | 2011-12-30 | 2013-07-03 | 江苏天晟药业有限公司 | Crocetin organic amine salt and preparation method thereof |
| CN105017059A (en) * | 2015-07-02 | 2015-11-04 | 深圳市新阳唯康科技有限公司 | Novel crystal form of niclosamide and preparation method thereof |
| US11793777B2 (en) | 2015-09-01 | 2023-10-24 | First Wave Bio, Inc. | Methods and compositions for treating conditions associated with an abnormal inflammatory response |
| CN106496060A (en) * | 2016-10-21 | 2017-03-15 | 恒诚制药集团淮南有限公司 | A kind of preparation method of niclosamide ethanolamine salt |
| CN106748863A (en) * | 2016-11-14 | 2017-05-31 | 苏州市罗森助剂有限公司 | A kind of improvement preparation method of niclosamide ethanolamine salt |
| WO2021076922A1 (en) * | 2019-10-18 | 2021-04-22 | First Wave Bio, Inc. | Pharmaceutical formulations |
| CN117597327A (en) * | 2019-10-18 | 2024-02-23 | 第一波动生物制药股份有限公司 | pharmaceutical preparations |
| US11564896B2 (en) | 2020-03-16 | 2023-01-31 | First Wave Bio, Inc. | Methods of treatment |
| US11744812B2 (en) | 2020-03-16 | 2023-09-05 | First Wave Bio, Inc. | Methods of treatment |
| WO2023249414A1 (en) * | 2022-06-22 | 2023-12-28 | 대웅바이오(주) | Method for producing benzoamine derivative |
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