CN102584811A - Method for preparing aztreonam - Google Patents
Method for preparing aztreonam Download PDFInfo
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- CN102584811A CN102584811A CN2011104609960A CN201110460996A CN102584811A CN 102584811 A CN102584811 A CN 102584811A CN 2011104609960 A CN2011104609960 A CN 2011104609960A CN 201110460996 A CN201110460996 A CN 201110460996A CN 102584811 A CN102584811 A CN 102584811A
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- aztreonam
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Abstract
The invention relates to a method for preparing aztreonam. The method comprises the following steps of: (1) reacting ceftazidime side chain acid with N-hydroxyl succinimide at the temperature of 0 and 5 DEG C to generate active ester; and (2) reacting the active ester with an aztreonam parent nucleus at the temperature of 0 and 10 DEG C, and refining to obtain the aztreonam. The method for preparing the aztreonam is high in stability and yield, economic and environment-friendly, and a solvent can be recycled.
Description
Technical field
The present invention relates to medical technical field, be specifically related to a kind of preparation method of aztreonam.
Background technology
Aztreonam is that first successfully is used for the anti-infectious microbiotic of clinical monobactams, and distinctive single ring architecture makes it improve no cross resistance to the beta-lactam enzyme stability.Aztreonam is not only the suitable medicine of nosocomial infection treatment due to the gram negative bacilli Resistant strain, and also can be to a certain extent as the substitute of aminoglycosides medicine.
Domestic production producer mainly contains Shanghai Sino-U.S. and executes more than 20 tame manufacturing enterprises such as your treasured, Shandong, Shandong are anti-, Harbin Pharmaceutical Group.Problems such as most of manufacturers are because technology barrier, and production cost is high, and dna purity is low, product stability is poor, pollution is big, production capacity is low.
Summary of the invention
In order to overcome above-mentioned defective, the present invention provides the preparation method of the aztreonam of a kind of economic environmental protection, good stability.
The preparation method of aztreonam of the present invention comprises the steps:
(1) ceftazime side-chain acid and N-hydroxy-succinamide generate active ester in 0～5 ℃ of reaction;
(2) active ester that generates and aztreonam parent nucleus get the aztreonam bullion in 0～10 ℃ of reaction, and crude product refining gets aztreonam.
Wherein, for next step successful reaction is carried out, can the solution that generate after the active ester be filtered, filter impurity, filter type is not limit, and for example can add zeyssatite etc. and carry out impurity absorption.
In addition, said aztreonam parent nucleus is claimed the little ring of aztreonam, aztreonam monocycle parent nucleus again, in the present invention, can select commercially available aztreonam parent nucleus.
Wherein, the mol ratio of said ceftazime side-chain acid and N-hydroxy-succinamide reaction is (0.5～1.5): 1.
In addition, the pH value of reaction is 7.5～8.5 described in the controlled step (1).
In addition, the present invention is a solvent with the methanol aqueous solution of 40～60 weight % in step (1).Solvent is used to dissolve ceftazime side-chain acid and N-hydroxy-succinamide; Solvent load does not have particular determination; But consider from the speed of reaction aspect; Preferred ceftazime side-chain acid of the consumption of solvent and N-hydroxy-succinamide gross weight 3～5 times, and solvent is recyclable, not only economy but also environmental protection.
In addition, the mol ratio of active ester and aztreonam parent nucleus is (0.5～1.5) described in the step (2): 1.
In addition, the pH value of reaction is 1.0～2.0 described in the controlled step (2).
In addition, in step (1) and step (2), regulate pH value with triethylamine or hydrochloric acid.
In addition, crude product refining is described in the step (2):
The aztreonam dissolving crude product in methyl alcohol, is heated to 50～60 ℃ of dissolvings fully, and the room temperature cooling gets aztreonam secondary bullion;
Aztreonam secondary dissolving crude product in absolute ethyl alcohol, is heated to 15～20 ℃ of dissolvings fully, is cooled to 0～5 ℃ of crystallization under stirring, the crystal filtration drying gets aztreonam.
In addition, said exsiccant temperature is 45～55 ℃.
The present invention is through ceftazime side-chain acid and N-hydroxy-succinamide reaction; Make active ester, active ester can make the aztreonam bullion with the reaction of aztreonam parent nucleus again, and wherein the aztreonam bullion is unstable; Can change aztreonam into beta crystal by alpha-crystal form through purification step; Improve its stability, therefore, the aztreonam using value after making with extra care is higher.This preparation method is simple, the aztreonam good stability that makes, yield height, the recyclable utilization of solvent, economic environmental protection.
Description of drawings
The aztreonam performance liquid chromatography spectrogram that Fig. 1 embodiment 1 makes.
Fig. 2 standard aztreonam performance liquid chromatography spectrogram.
Embodiment
Used each raw material sources are following among the embodiment of preparation aztreonam.
The ceftazime side-chain acid: Wuhan City, Hubei prestige is along reaching biochemical industry ltd system;
N-hydroxy-succinamide: emerging biochemical reagents ltd of Shanghai section;
Aztreonam parent nucleus: Chongqing Borning Chemical & Industrial Co., Ltd.;
Embodiment 1
With in the 5000ml there-necked flask that TM, prolong, mechanical stirrer are installed; Add the methanol solution of 358g 40%, open stirring, icy salt solution is cooled to 0 ℃; After adding 50g ceftazime side-chain acid, the dissolving of 24gN-HOSu NHS, be 7.5 with triethylamine regulation system PH.Reaction solution was stirred 1 hour, add hydrochloric acid, regulating PH is 4.0, adds 5g zeyssatite and stirs 10 minutes, and suction filtration obtains active ester.In filtrating, adding hydrochloric acid accent PH is 1.0, treats that solution is slightly muddy, stops to stir, and leaves standstill 10 minutes, adds 30g aztreonam parent nucleus, is cooled to 10 ℃ of stirrings 3 hours.Suction filtration, 50 ℃ of vacuum-dryings get aztreonam bullion 63.8g.
With 63.8g aztreonam bullion, add in the 460ml methyl alcohol, be heated to 50 ℃ of stirring and dissolving, suction filtration while hot is after filtrating under agitation is cooled to room temperature; Suction filtration gets the secondary bullion, in the secondary bullion, adds the 460ml absolute ethyl alcohol, is heated to 15 ℃ of dissolvings; Heated and stirred, filtered while hot, filtrating is cooled to 5 ℃ of crystallizations under stirring, and centrifugally gets rid of filter; Filter cake gets aztreonam 51.2g, yield 78% with twice, 50 ℃ of vacuum-drying of absolute ethanol washing 6 hours.
The aztreonam sample that mensuration makes under the same terms and the performance liquid chromatography of standard aztreonam, like Fig. 1 and shown in Figure 2, identical 9.070min and the 9.217min of being respectively of characteristic peak RT, the aztreonam that then makes is consistent with standard aztreonam structure.
Embodiment 2
With in the 5000ml there-necked flask that TM, prolong, mechanical stirrer are installed; Add the methanol solution of 365g 50%, open stirring, icy salt solution is cooled to 5 ℃; After adding 20g ceftazime side-chain acid, the dissolving of 11.5gN-HOSu NHS, be 8.5 with triethylamine regulation system PH.Reaction solution was stirred 1 hour, add hydrochloric acid, regulating PH is 4.0, adds 5g zeyssatite and stirs 10 minutes, and suction filtration obtains active ester.In filtrating, adding hydrochloric acid accent PH is 2.0, treats that solution is slightly muddy, stops to stir, and leaves standstill 10 minutes, adds 20g aztreonam parent nucleus, is cooled to 5 ℃ of stirrings 3 hours.Suction filtration, 50 ℃ of vacuum-dryings get aztreonam bullion 20.12g.
With 20.12g aztreonam bullion, add in the 500ml methyl alcohol, be heated to 60 ℃ of stirring and dissolving, suction filtration while hot, the room temperature cooling under agitation of filtrating; Suction filtration gets the secondary bullion, in the secondary bullion, adds the 500ml absolute ethyl alcohol, is heated to 20 ℃ of dissolvings; Heated and stirred, filtered while hot, filtrating is cooled to 0 ℃ of crystallization under stirring, and centrifugally gets rid of filter; Filter cake gets aztreonam 18g, yield 83% with twice, 45 ℃ of vacuum-drying of absolute ethanol washing 6 hours.
Embodiment 3
With in the 5000ml there-necked flask that TM, prolong, mechanical stirrer are installed; Add the methanol solution of 340g 60%, open stirring, icy salt solution is cooled to 3 ℃; After adding 49.4g ceftazime side-chain acid, the dissolving of 12.5gN-HOSu NHS, be 8.0 with triethylamine regulation system PH.Reaction solution was stirred 1 hour, add hydrochloric acid, regulating PH is 4.0, adds 5g zeyssatite and stirs 10 minutes, and suction filtration obtains active ester.In filtrating, adding hydrochloric acid accent PH is 1.5, treats that solution is slightly muddy, stops to stir, and leaves standstill 10 minutes, adds 25g aztreonam parent nucleus, is cooled to 0 ℃ of stirring 3 hours.Suction filtration, 50 ℃ of vacuum-dryings get aztreonam bullion 38.07g.
With 38.07g aztreonam bullion, add in the 500ml methyl alcohol, be heated to 55 ℃ of stirring and dissolving, suction filtration while hot is after filtrating under agitation is cooled to room temperature; Suction filtration gets the secondary bullion, in the secondary bullion, adds the 500ml absolute ethyl alcohol, is heated to 20 ℃ of dissolvings; Heated and stirred, filtered while hot, filtrating is cooled to 0 ℃ of crystallization under stirring, and centrifugally gets rid of filter; Filter cake gets aztreonam 35.26g, yield 81% with twice, 55 ℃ of vacuum-drying of absolute ethanol washing 6 hours.
Embodiment 4
With in the 5000ml there-necked flask that TM, prolong, mechanical stirrer are installed; Add the methanol solution of 320g 60%, open stirring, icy salt solution is cooled to 0 ℃; After adding 32.9g ceftazime side-chain acid, the dissolving of 10.9gN-HOSu NHS, be 7.5 with triethylamine regulation system PH.Reaction solution was stirred 1 hour, add hydrochloric acid, regulating PH is 4.0, adds 5g zeyssatite and stirs 10 minutes, and suction filtration obtains active ester.In filtrating, add hydrochloric acid and transfer PH1.0, treat that solution is slightly muddy, stop to stir, left standstill 10 minutes, add 18g aztreonam parent nucleus, be cooled to below 10 ℃ and stirred 3 hours.Suction filtration, 50 ℃ of vacuum-dryings get aztreonam bullion 36.7g.
With 36.7g aztreonam bullion, add in the 460ml methyl alcohol, be heated to 50 ℃ of stirring and dissolving, suction filtration while hot is after filtrating under agitation is cooled to room temperature; Suction filtration gets the secondary bullion, in the secondary bullion, adds the 460ml absolute ethyl alcohol, is heated to 15 ℃ of dissolvings; Heated and stirred, filtered while hot, filtrating is cooled to 5 ℃ of crystallizations under stirring, and centrifugally gets rid of filter; Filter cake gets aztreonam 34.3g, yield 78% with twice, 45 ℃ of vacuum-drying of absolute ethanol washing 6 hours.
Two, performance test
The character of the aztreonam that makes with standard detection embodiment 1～4 shown in Chinese Pharmacopoeia 2010 aztreonam, the result is as shown in the table.
Table 1, embodiment 1～4 aztreonam test result
As shown in table 1, the aztreonam that the present invention makes is tested after placing 3～6, and each item index no change was placed after 9～12 months, and each item index does not have considerable change.The aztreonam extended storage stability that the present invention makes is very excellent.
Claims (9)
1. the preparation method of an aztreonam is characterized in that, comprises the steps:
(1) ceftazime side-chain acid and N-hydroxy-succinamide generate active ester in 0～5 ℃ of reaction;
(2) active ester that generates and aztreonam parent nucleus get the aztreonam bullion in 0～10 ℃ of reaction, and crude product refining gets aztreonam.
2. preparation method according to claim 1 is characterized in that, the mol ratio of said ceftazime side-chain acid and N-hydroxy-succinamide reaction is (0.5～1.5): 1.
3. preparation method according to claim 1 is characterized in that, in step (1), the pH value of said reaction is 7.5～8.5.
4. preparation method according to claim 1 is characterized in that in step (1), is that 40～60% methanol aqueous solution is a solvent with weight percentage.
5. preparation method according to claim 1 is characterized in that, in step (2), the mol ratio of said active ester and aztreonam parent nucleus is (0.5～1.5): 1.
6. preparation method according to claim 1 is characterized in that, in step (2), the pH value of said reaction is 1.0～2.0.
7. preparation method according to claim 1 is characterized in that, in step (1) and step (2), regulates pH value with triethylamine or hydrochloric acid.
8. preparation method according to claim 1 is characterized in that, the crude product refining described in the step (2) is:
The aztreonam dissolving crude product in methyl alcohol, is heated to 50～60 ℃ of dissolvings, and the room temperature cooling gets aztreonam secondary bullion;
Aztreonam secondary dissolving crude product in absolute ethyl alcohol, is heated to 15～20 ℃ of dissolvings, is cooled to 0～5 ℃ of crystallization under stirring, the crystal filtration drying gets aztreonam.
9. preparation method according to claim 8 is characterized in that, said exsiccant temperature is 45～55 ℃.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011104609960A CN102584811A (en) | 2011-12-29 | 2011-12-29 | Method for preparing aztreonam |
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| CN2011104609960A CN102584811A (en) | 2011-12-29 | 2011-12-29 | Method for preparing aztreonam |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044415A (en) * | 2012-12-17 | 2013-04-17 | 浙江华方药业有限责任公司 | Synthesis method for aztreonam |
| CN105418474A (en) * | 2015-12-21 | 2016-03-23 | 山东金城医药化工股份有限公司 | Refining method for main ring of aztreonam |
| CN108997327A (en) * | 2018-07-12 | 2018-12-14 | 福安药业集团重庆博圣制药有限公司 | The preparation method of aztreonam ethyl ester |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4775670A (en) * | 1980-09-29 | 1988-10-04 | E. R. Squibb & Sons, Inc. | 2-oxo-1-azetidinesulfonic acid salts |
| KR100472048B1 (en) * | 2002-07-11 | 2005-03-08 | 종근당바이오 주식회사 | Novel method for producing Aztreonam |
| CN101171251A (en) * | 2005-05-09 | 2008-04-30 | 西科尔公司 | Process for making aztreonam |
-
2011
- 2011-12-29 CN CN2011104609960A patent/CN102584811A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4775670A (en) * | 1980-09-29 | 1988-10-04 | E. R. Squibb & Sons, Inc. | 2-oxo-1-azetidinesulfonic acid salts |
| KR100472048B1 (en) * | 2002-07-11 | 2005-03-08 | 종근당바이오 주식회사 | Novel method for producing Aztreonam |
| CN101171251A (en) * | 2005-05-09 | 2008-04-30 | 西科尔公司 | Process for making aztreonam |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044415A (en) * | 2012-12-17 | 2013-04-17 | 浙江华方药业有限责任公司 | Synthesis method for aztreonam |
| CN105418474A (en) * | 2015-12-21 | 2016-03-23 | 山东金城医药化工股份有限公司 | Refining method for main ring of aztreonam |
| CN108997327A (en) * | 2018-07-12 | 2018-12-14 | 福安药业集团重庆博圣制药有限公司 | The preparation method of aztreonam ethyl ester |
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Application publication date: 20120718 |