CN1626506A - Preparing niclosamide in high purity and high yield - Google Patents
Preparing niclosamide in high purity and high yield Download PDFInfo
- Publication number
- 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
- Authority
- CN
- China
- Prior art keywords
- niclosamide
- acid
- amine
- manufacture method
- described manufacture
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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 |
Applications Claiming Priority (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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1626506A true CN1626506A (en) | 2005-06-15 |
Family
ID=34764276
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200410059115 Pending CN1626506A (en) | 2004-08-10 | 2004-08-10 | Preparing niclosamide in high purity and high yield |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1626506A (en) |
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 (9)
| 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 |
| 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 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104230803B (en) | Preparation method of hydroxychloroquine sulfate | |
| CN1626506A (en) | Preparing niclosamide in high purity and high yield | |
| CN102050781A (en) | Industrial preparation method of hydroxychloroquine sulfate | |
| US8680329B2 (en) | Process for preparation of α-ketoglutaric acid | |
| CN110903251B (en) | Preparation method of 2-amino-4, 6-dimethoxypyrimidine | |
| US9440918B2 (en) | Method for purifying (S)-Oxiracetam | |
| NO150668B (en) | PROCEDURE FOR THE PREPARATION OF A MONOLITIC MACHINE PART WITH PARTS OF DIFFERENT ALLOY COMPOSITION BY POWDER METAL SURGERY | |
| CN112574049A (en) | Novel method for preparing phenylglycine by using hydrocyanic acid | |
| CN112010856A (en) | Telescoping process method for preparing folic acid by using microchannel reaction | |
| CN111470963A (en) | Method for preparing phenoxyacetic acid and 2, 4-dichlorophenoxyacetic acid | |
| EP2743258A1 (en) | Method for purifying levo-oxiracetam | |
| CN113461529B (en) | Preparation method of 2-methyl-4-chlorophenoxyacetic acid isooctyl ester | |
| EP2809644A1 (en) | Method and system for producing nitrobenzene | |
| CN100395230C (en) | Method for preparing high-purity gahapentin | |
| CN108863875B (en) | Method for purifying thiourea and thiourea | |
| CN102432518A (en) | Synthetic method of 3-methylindole | |
| CN106432089B (en) | The synthetic method of Maxamine | |
| CN108997165B (en) | Method for synthesizing balsalazide disodium | |
| CN112979550A (en) | Method for preparing 1-methyl-5-hydroxypyrazole by using microchannel reactor | |
| CN107827821B (en) | Continuous flow clean production process of pyrazolone series products | |
| CN106316861B (en) | A kind of method for preparing double benzene bacterium amine | |
| CN111646913A (en) | Preparation method of ammonia-process betaine | |
| CN119409599A (en) | Continuous synthesis method and equipment of methyl diphenyl methane dicarbamate | |
| CN112300151B (en) | Preparation method of milpitant intermediate | |
| CN118084912A (en) | Preparation method of 2, 6-diaminopurine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C57 | Notification of unclear or unknown address | ||
| DD01 | Delivery of document by public notice |
Addressee: Li Genrong Document name: Notification that Application Deemed to be Withdrawn |
|
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20050615 |
