CN101171251A - Process for making aztreonam - Google Patents
Process for making aztreonam Download PDFInfo
- Publication number
- CN101171251A CN101171251A CNA200680015648XA CN200680015648A CN101171251A CN 101171251 A CN101171251 A CN 101171251A CN A200680015648X A CNA200680015648X A CN A200680015648XA CN 200680015648 A CN200680015648 A CN 200680015648A CN 101171251 A CN101171251 A CN 101171251A
- Authority
- CN
- China
- Prior art keywords
- described method
- aztreonam
- temperature
- reaction mixture
- solvent
- 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
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A simplified process for the one-pot preparation of aztreonam, using azetidine and TAEM as starting materials, without the intermediary separation of t-butyl-aztreonam is provided.
Description
Related application
The application has required the rights and interests of No. the 60/679th, 313, the U.S. Provisional Patent Application submitted respectively on May 9th, 2005 and on May 17th, 2005 and the 60/681st, No. 808, and their content is incorporated herein by reference in full at this.
Technical field
The present invention relates to the method for a kind of synthetic aztreonam (aztreonam).Especially, the present invention relates to a kind of " one pot " method when being used for synthetic aztreonam.
Background technology
Aztreonam is a kind of single Batan class microbiotic; its chemistry [3S-[3 α (Z) by name; 4 β]]-3-[[(2-amino-4-thiazolyl) [(1-carboxyl-1-methyl ethoxy) imino-] ethanoyl] amino]-4-methyl-2-oxo-1-azetidin alkyl sulfonic acid, its structure is as follows:
United States Patent (USP) the 4th, 775, the method that discloses a kind of with the following formula: compound acidylate No. 670:
This acidylate comprises makes compound and carboxylic acid or corresponding carboxylic acid halogenide or carboxylic acid anhydride (R
1-OH) carbodiimide for example dicyclohexylcarbodiimide and the material that can form active ester on the spot for example the N-hydroxybenzotriazole in the presence of react.U.S.4, the deprotection in 775,670 react under anhydrous condition in the presence of methyl-phenoxide and carry out by acidylating product and trifluoroacetic acid.Employed reagent is poisonous and cost an arm and a leg in this method.
United States Patent (USP) the 4th, 946 discloses a kind of alternative method of crystalline anhydrous aztreonam and a kind of crystalline, anhydrous form of antiseptic-germicide of preparing No. 838.The complex synthetic route of describing in this patent comprises, for example, with trifluoroacetic acid in methyl-phenoxide in unconditional hydrolysis diphenyl protecting group down with preparation α-type aztreonam.α-type is carried out recrystallization with preparation β-type aztreonam in anhydrous organic solvent.
United States Patent (USP) 5,254,681 disclose a kind of method for preparing aztreonam, and it comprises with 2-(2-amino-4-thiazolyl)-2-(Z)-(the inferior hydrogen base of alkoxyl group) acetate acidylate azetidine in the presence of 1-hydroxyl-benzotriazole and dicyclohexylcarbodiimide.The reagent that uses in this method is poisonous and cost an arm and a leg, and they also are difficult to handle.
PCT discloses WO and discloses a kind of method for preparing aztreonam for No. 2004/013133; it is at elevated temperatures by ester and aqueous acid are reacted and hydrolysis [3S-[3 α (Z), 4 β]]-3-[[(2-amino-4-thiazolyl) [(1-tert-butoxycarbonyl-1-methyl ethoxy) imino-] ethanoyl] amino]-ester group of 4-methyl-2-oxo-1-azo-cycle butane sulfonic acid (t-bu aztreonam).This application has also been described azetidine and TAEM and acetonitrile and alkali, randomly other solvent for example THF in the presence of the condensation carried out, thereby obtain t-bu aztreonam.
Further the method for simplifying is desired.The present invention just provides such simplified method.
Summary
The invention provides a kind of one pot of method for preparing aztreonam.This method is included in C
1-C
3Under the existence of tertiary amine and the solvent that is selected from acetone, 2-butanone and hexone (MIBK), make azetidine and TAEM chemical combination, thereby obtain reaction mixture; Thereby add first mineral acid and obtain about 4.5 to about 7.5 pH with precipitation MBT; Separate MBT; Add the entry and second mineral acid to obtain pH less than about 2; Heating; And cool off to obtain aztreonam, wherein first and second mineral acids can be identical or different.
Describe in detail
The present invention relates to prepare aztreonam with one kettle way.This method is included in C
1-C
3Thereby make azetidine and TAEM carry out condensation under the existence of tertiary amine and solvent and obtain t-bu aztreonam, obtain aztreonam thereby described t-bu aztreonam further is hydrolyzed.Before hydrolysing step, from reaction mixture, isolate the by product MBT that during azetidine and TAEM condensation, obtains.Present method has been simplified PCT and is disclosed the method disclosed in WO2004/013133 number, because present method has reduced employed number of solvents in the condensation step, and has used one kettle way.Present method is by using acetone, 2-butanone or hexone (MIBK) and C
1-C
3The mixed solvent of tertiary amine replaces solvent acetonitrile and is further simplified, and described mixed solvent can dissolve TAEM and aztreonam simultaneously, thereby, obviously reduced the required time has been finished in demand and the reaction of excessive TAEM.Method has been simplified in removing of MBT by product, so just need not extract t-bu aztreonam in the mixture of ethyl acetate and water.
One kettle way has been avoided the separation to t-bu aztreonam, save the time, reduced waste, and improved the throughput of factory, so just avoided that part of product that in the separation of t-bu aztreonam, loses, and these aztreonam can remove to carry out the next procedure of method.
As used herein; term " t-bu aztreonam " is meant compound [3S-[3 α (Z), 4 β]]-3-[[(2-amino-4-thiazolyl) [(1-tertbutyloxycarbonyl-1-methyl ethoxy) imino-] ethanoyl] amino]-4-methyl-2-oxo-1-azetidin alkyl sulfonic acid.
As used herein, term " azetidine " is meant the compound with following chemical formula:
As used herein, term " MBT " is meant the by product with following chemical formula:
As used herein, term " TAEM " is meant the compound with following chemical formula:
As used herein, term " C
1-C
3Tertiary amine " be meant a kind of molecule that contains the nitrogen-atoms that links to each other with three chains, wherein each chain can be C independently
1-C
3Alkyl.
The invention provides a kind of one pot of method for preparing aztreonam.This method is included in C
1-C
3Under the existence of tertiary amine and the solvent that is selected from acetone, 2-butanone and hexone (MIBK), make azetidine and TAEM combination, thereby obtain reaction mixture; Thereby add first mineral acid and obtain about 4.5 to about 7.5 pH with precipitation MBT; Separate MBT; Add the entry and second mineral acid to obtain pH less than about 2; Heating; And thereby cooling obtains aztreonam.
Preferably, solvent is an acetone.Preferably, C
1-C
3Tertiary amine is a triethylamine.Preferably, this method at first comprises C
1-C
3Tertiary amine and solvent arrive under about 30 ℃ temperature at about-5 ℃, more preferably mix under about 15 ℃ temperature at about 10 ℃.Preferably, azetidine is joined C
1-C
3In the mixture of tertiary amine and solvent, then add TAEM.Preferably, TAEM progressively adds.Preferably, under agitation azetidine and TAEM are joined C
1-C
3In the mixture of tertiary amine and solvent.Preferably, stir about is 30 minutes.Preferably, will comprise: C
1-C
3The reaction mixture of tertiary amine, solvent, azetidine and TAEM kept about 4 hours.Preferably, before adding first mineral acid, in reaction mixture, add entry.Preferably, after adding entry, from reaction mixture, remove and desolvate.Preferably, desolvate by distilling to remove.Preferably, water distills.Preferably, before separating MBT, the pH of reaction mixture is about 5 to about 6, more preferably, is about 5.5.Preferably, first and second mineral acids are selected from HCl, H
2SO
4And H
3PO
4More preferably, at least a in first and second mineral acids is HCl.Preferably, before separating MBT, the acidifying reaction mixture further is cooled to be lower than about 5 ℃ temperature.Preferably, by filtering separation MBT.Preferably, pH is about 1 to about 2 after adding entry and mineral acid, and more preferably, pH is about 1.5.Preferably, thus being heated to about 50 ℃ obtains reaction mixture to about 70 ℃ temperature.More preferably, be heated to about 60 ℃ temperature.Preferably, after the heating, this method comprises that further maintenance about 4 by about 5 hours, more preferably, kept about 5 hours.Preferably, thus being cooled to about 5 ℃ obtains precipitation to about 0 ℃ temperature.Preferably, cooled off about 4 to about 8 hours, more preferably, cooled off about 5 hours.
Preferably, this method further comprises the recovery aztreonam.Preferably, described recovery comprises filtration, washing, also filters with anhydrous polar organic solvent slurryization.After reclaiming, obtain wet aztreonam.Preferably, anhydrous polar organic solvent is dehydrated alcohol or Virahol, methyl alcohol.
Preferably, aztreonam is by further crystallization.The washing aztreonam avoids drying process to go wrong before crystallization.Used anhydrous polar organic solvent to wash to avoid during drying destruction, and removed the solvent of any trace in the purge process product, thereby, the problem of cleaning reactor reduced.Crystallization method comprises wet aztreonam is mixed with organic ammonium salt, thus and adding ethanol, methyl alcohol or Virahol acquisition solution.Thereby described solution further carries out acidifying with mineral acid obtains about 1 to about 3 pH, is cooled to about 10 ℃ to about-10 ℃ temperature, filters and drying.Preferably, described ammonium salt is an ammonium acetate.Preferably, before adding ethanol, methyl alcohol or Virahol, reaction mixture is cooled to about 5 ℃ arrives about 0 ℃ temperature.Preferably, with about 3 hours of refrigerative solution stirring.Preferably, after adding second mineral acid and before cooling, to reaction mixture kind crystalline substance.Preferably, the reaction mixture with kind of crystalline substance kept about 6 hours under about 5 ℃ temperature at about 0 ℃.Preferably, the acidifying reaction mixture is cooled to about 5 ℃ to about 0 ℃.
Embodiment
The present invention is described with reference to some preferred embodiment, and by with reference to this specification sheets, other embodiment also is conspicuous to those skilled in the art.The present invention is by further being defined with reference to following examples, and these embodiment describe the preparation and the using method of the present composition in detail.Obviously, those skilled in the art can carry out many improvement to raw material and method without departing from the present invention.
Embodiment 1
The 50ml sample of triethylamine is joined in three mouthfuls of glass reactors of 0.5l that condenser and mechanical stirrer and 100ml acetone are housed, and it is cooled to about 10 ℃ to about 15 ℃.Under mixing, the 50g azetidine is joined in the reaction mixture, then add 43g TAEM.Continue to stir at least about 30 minutes, up to the color disappearance of initial formation.Add other two parts of 43g TAEM then in the same way.Reaction generally after about four hours, adds entry and reacts with cancellation after finishing, and removes acetone by distilling with water.With HCl reactive material is acidified to pH about 5.5 and cooling.Mercaptobenzothiazole (MBT) precipitates, and obtains separating by filtration.
The pH regulator of reactive material that will contain t-bu aztreonam with HCl is to about 1.5, and dilutes with the water of about 400ml.Reactive material is heated to about 60 ℃ and kept about 5 hours under this temperature.After the end of chromatogram checking deprotection reaction, reactive material slowly is cooled to about 0 ℃ to about 5 ℃ in about 5 hours time.Aztreonam precipitates, and filters and washed several times with water.Filter cake is feeded again,, filter once more and blowing with the slurrying of 240ml dehydrated alcohol.Obtain the wet aztreonam crude product of about 140g.
Embodiment 2
Wet aztreonam of 140g and 70g ammonium acetate are joined in 21 3 mouthfuls of glass reactors that condenser and mechanical stirrer are housed, be cooled to about 0 ℃ to about 5 ℃.Add after the 1.2l ethanol, the clear solution that is produced was mixed 3 hours under identical temperature.The HCl solution that slowly adds about 15ml 33% up to the pH that realizes about 1 to about 3, kept about 6 hours under about 5 ℃ temperature in addition to reaction mixture kind crystalline substance and at about 0 ℃.Then aztreonam is filtered and drying, produced 60g exsiccant aztreonam, overall yield is about 50%.
Though obvious invention disclosed herein is suitable for realizing above-described purpose, can predicts those skilled in the art and can make multiple improvement and embodiment.Therefore, appended claim intention improvement and the embodiment that all are such covers within connotation of the present invention and the scope.
Claims (35)
1. one pot of method for preparing aztreonam, it is included in C
1-C
3Under the existence of tertiary amine and the solvent that is selected from acetone, 2-butanone and methyl isopropyl ketone (MIBK), azetidine is combined with TAEM, thereby obtain reaction mixture; Thereby add first mineral acid to obtain about 4.5 to about 7.5 pH precipitation MBT; Separate MBT; Add the entry and second mineral acid, to obtain pH less than about 2; Heating; And thereby cooling obtains aztreonam; Wherein first and second mineral acids can be identical or different.
2. the method for claim 1, wherein said solvent is an acetone.
3. as claim 1 and 2 any described method, wherein C
1-C
3Tertiary amine is a triethylamine.
4. as any described method of claim 1 to 3, wherein at first with C
1-C
3Tertiary amine mixes under about 30 ℃ temperature at about-5 ℃ with solvent.
5. method as claimed in claim 4 is wherein at first with C
1-C
3Tertiary amine mixes under about 15 ℃ temperature at about 10 ℃ with solvent.
6. as claim 4 and 5 any described methods, wherein to C
1-C
3Add azetidine in the mixture of tertiary amine and solvent.
7. as any described method of claim 1 to 6, wherein after adding azetidine, add TAEM.
8. as any described method of claim 1 to 7, wherein TAEM progressively adds.
9. as any described method of claim 1 to 8, wherein under agitation azetidine and TAEM are joined C
1-C
3In the mixture of tertiary amine and solvent.
10. as any described method of claim 1 to 9, wherein before adding first mineral acid, in reaction mixture, add entry.
11., wherein after adding entry, from reaction mixture, remove and desolvate as any described method of claim 1 to 10.
12. method as claimed in claim 11 is wherein removed by distillation and is desolvated.
13. as any described method of claim 1 to 12, wherein pH is about 5 to about 6 before separating MBT.
14. as any described method of claim 1 to 13, wherein first and second mineral acids are independently selected from HCl, H
2SO
4And H
3PO
4
15. method as claimed in claim 14, wherein at least a in first and second mineral acids is HCl.
16., wherein, before separating MBT, the acidifying reaction mixture further is cooled to be lower than about 5 ℃ temperature as any described method of claim 1 to 15.
17. as any described method of claim 1 to 16, wherein by filtering separation MBT.
18. as any described method of claim 1 to 17, wherein the pH after adding the entry and second mineral acid is about 1 to about 2.
19. method as claimed in claim 18, wherein the pH after adding entry and mineral acid is about 1.5.
20. as any described method of claim 1 to 19, wherein heating is to arrive about 70 ℃ temperature to about 50 ℃.
21. method as claimed in claim 20, wherein heating is to about 60 ℃ temperature.
22. as any described method of claim 1 to 21, wherein this method comprises that further maintenance about 4 was by about 5 hours after heating.
23. as any described method of claim 1 to 22, wherein this method further comprises about 5 hours of maintenance after heating.
24. as any described method of claim 1 to 23, wherein cooling is to arrive about 0 ℃ temperature to obtain precipitation to about 5 ℃.
25. method as claimed in claim 24 was wherein cooled off about 4 to about 8 hours.
26. as any described method of claim 1 to 25, wherein this method further comprises the recovery aztreonam.
27. method as claimed in claim 26, wherein reclaim comprise filtration, washing, with anhydrous polar organic solvent pulp and filtration.
28. method as claimed in claim 27, wherein anhydrous polar organic solvent are dehydrated alcohol or Virahol, methyl alcohol.
29. as any described method of claim 1 to 26, wherein this method further comprises by aztreonam is combined with organic ammonium salt, add ethanol, methyl alcohol or Virahol to obtain solution, with the mineral acid souring soln to obtain about 1 to about 3 pH, be cooled to about 10 ℃ to about-10 ℃ temperature, thereby filtration and drying are carried out crystallization to aztreonam.
30. method as claimed in claim 29, wherein ammonium salt is an ammonium acetate.
31., wherein, before adding ethanol, methyl alcohol or Virahol, reaction mixture is cooled to about 5 ℃ arrives about 0 ℃ temperature as claim 29 and 30 any described methods.
32. method as claimed in claim 31 wherein stirs refrigerative solution.
33. as any described method of claim 29 to 32, before wherein after adding second mineral acid, cooling off, to reaction mixture kind crystalline substance.
34. method as claimed in claim 33 wherein will be planted brilliant reaction mixture and be kept about 6 hours under about 5 ℃ temperature at about 0 ℃.
35., wherein the acidifying reaction mixture is cooled to about 5 ℃ to about 0 ℃ as the described method of claim 29 to 34.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US67931305P | 2005-05-09 | 2005-05-09 | |
| US60/679,313 | 2005-05-09 | ||
| US60/681,808 | 2005-05-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101171251A true CN101171251A (en) | 2008-04-30 |
Family
ID=39391338
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA200680015648XA Pending CN101171251A (en) | 2005-05-09 | 2006-05-09 | Process for making aztreonam |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101171251A (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101412715B (en) * | 2008-12-16 | 2010-04-14 | 海南百那医药发展有限公司 | Aztreonam compound and preparation thereof |
| CN101830895A (en) * | 2010-04-16 | 2010-09-15 | 海南新中正制药有限公司 | Aztreonam anhydrous crystal compound and preparation method thereof |
| CN102127068A (en) * | 2010-12-31 | 2011-07-20 | 山西普德药业股份有限公司 | Method for synthesizing aztreonam compound |
| CN102584811A (en) * | 2011-12-29 | 2012-07-18 | 蚌埠丰原涂山制药有限公司 | Method for preparing aztreonam |
| CN103570707A (en) * | 2012-07-21 | 2014-02-12 | 重庆圣华曦药业股份有限公司 | Improved synthetic method of aztreonam |
| CN105001215A (en) * | 2015-08-03 | 2015-10-28 | 青岛蓝盛洋医药生物科技有限责任公司 | Aztreonam compound serving as sterilization medicine and preparation method thereof |
| CN105017241A (en) * | 2015-06-24 | 2015-11-04 | 山东罗欣药业集团股份有限公司 | Aztreonam compound and preparation thereof |
| CN105085511A (en) * | 2015-05-29 | 2015-11-25 | 石药集团中诺药业（石家庄）有限公司 | Novel aztreonam compound |
| CN111448182A (en) * | 2017-10-02 | 2020-07-24 | 阿里萨制药有限公司 | Aztreonam derivative and application thereof |
-
2006
- 2006-05-09 CN CNA200680015648XA patent/CN101171251A/en active Pending
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101412715B (en) * | 2008-12-16 | 2010-04-14 | 海南百那医药发展有限公司 | Aztreonam compound and preparation thereof |
| CN101830895A (en) * | 2010-04-16 | 2010-09-15 | 海南新中正制药有限公司 | Aztreonam anhydrous crystal compound and preparation method thereof |
| CN102127068A (en) * | 2010-12-31 | 2011-07-20 | 山西普德药业股份有限公司 | Method for synthesizing aztreonam compound |
| CN102127068B (en) * | 2010-12-31 | 2012-08-29 | 山西普德药业股份有限公司 | Method for synthesizing aztreonam compound |
| CN102584811A (en) * | 2011-12-29 | 2012-07-18 | 蚌埠丰原涂山制药有限公司 | Method for preparing aztreonam |
| CN103570707B (en) * | 2012-07-21 | 2016-03-09 | 重庆圣华曦药业股份有限公司 | A kind of synthetic method of aztreonam of improvement |
| CN103570707A (en) * | 2012-07-21 | 2014-02-12 | 重庆圣华曦药业股份有限公司 | Improved synthetic method of aztreonam |
| CN105085511A (en) * | 2015-05-29 | 2015-11-25 | 石药集团中诺药业（石家庄）有限公司 | Novel aztreonam compound |
| CN105085511B (en) * | 2015-05-29 | 2018-04-06 | 石药集团中诺药业（石家庄）有限公司 | A kind of new aztreonam compound |
| CN105017241A (en) * | 2015-06-24 | 2015-11-04 | 山东罗欣药业集团股份有限公司 | Aztreonam compound and preparation thereof |
| CN105017241B (en) * | 2015-06-24 | 2018-03-06 | 山东罗欣药业集团股份有限公司 | A kind of aztreonam compound and its preparation |
| CN105001215A (en) * | 2015-08-03 | 2015-10-28 | 青岛蓝盛洋医药生物科技有限责任公司 | Aztreonam compound serving as sterilization medicine and preparation method thereof |
| CN111448182A (en) * | 2017-10-02 | 2020-07-24 | 阿里萨制药有限公司 | Aztreonam derivative and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101171251A (en) | Process for making aztreonam | |
| JP5247728B2 (en) | Method for producing benzimidazole derivative | |
| KR960007865B1 (en) | Organic salts of physostigmine derivatives, preparation method thereof and pharmaceutical composition comprising the same | |
| HRP20010514A2 (en) | Telmisartan polymorphs, methods for producing same and their use in the preparation of a medicament | |
| CN102985416A (en) | Process of preparing a thrombin specific inhibitor | |
| JP6170059B2 (en) | Prevention of crystallization solvents in the production of polyphosphite ligands | |
| US20040242556A1 (en) | Novel crystalline form of cefdinir | |
| CN107922352A (en) | The method for preparing protein deacetylase inhibitors | |
| AU2008321691A1 (en) | Manufacturing method of 2-hydroxy-5-phenylalkylaminobenzoic acid derivatives and their salts | |
| CN111072633A (en) | Preparation method of esomeprazole magnesium trihydrate | |
| EP1888576B1 (en) | Process for making aztreonam | |
| CN102653525B (en) | Process for preparing bendamustine alkyl esters, bendamustine and derivatives thereof | |
| WO2017205622A1 (en) | Method of making benznidazole | |
| WO2009024685A1 (en) | Method for producing fenofibrate | |
| CN112272665B (en) | Process for preparing ritalst | |
| CN1149202C (en) | Improved methodf or preparing 4-amino-1,2,4-triazoline-5-one | |
| JPS58172344A (en) | Manufacture of phenylalkanoic acid | |
| JP4307594B2 (en) | Method for isolating 1- [N2-((S-ethoxycarbonyl) -3-phenylpropyl) -N6-trifluoroacetyl] -L-lysyl-L-proline and isolated product thereof | |
| CN112341406B (en) | Synthesis method of trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantane-1-ol | |
| JPH05221963A (en) | Urea fusion process for synthesis of 3-phenoxy- 1-azetidinecarboxyamide | |
| CN108863946A (en) | A kind of preparation method of dibazol impurity reference substance | |
| JPH07267950A (en) | Production of 5-chloro-n-(4,5-dihydro-1h-imidazol-2-yl)-2,1,3-benzothiadiazole-4-amine or its acid-added salt | |
| IE54471B1 (en) | Process for the preparation of substituted chloroacetanilides | |
| CN118324683A (en) | Preparation method of 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylic acid allyl ester | |
| CN116768817A (en) | 3-Aminobenzisothiazole derivatives and production methods thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20080430 |