CN101195618A - Method for producing beta crystal system anhydrous aztreonam - Google Patents
Method for producing beta crystal system anhydrous aztreonam Download PDFInfo
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- CN101195618A CN101195618A CNA2006101610715A CN200610161071A CN101195618A CN 101195618 A CN101195618 A CN 101195618A CN A2006101610715 A CNA2006101610715 A CN A2006101610715A CN 200610161071 A CN200610161071 A CN 200610161071A CN 101195618 A CN101195618 A CN 101195618A
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Abstract
The invention relates to a production method of anhydrous beta-type aztreonam, which comprises dissolving alpha-crystal-system aztreonam in the mixture of absolute ethyl alcohol and acetone at -10-+25DEG C, filtering without germ, heating the solution to 30-55DEG C, or seriously mixing to obtain anhydrous beta-type aztreonam crystals.
Description
Technical field
The present invention relates to a kind of anhydrous beta crystal formation aztreonam crystalline production method.
Background technology
Aztreonam shown in the molecular formula I (Aztreonam) is a kind of monocycle beta-lactam antibiotics of synthetic, and Gram-negative bacteria is had anti-microbial activity.
Molecular formula I
Some reference have been reported the technology of preparing of aztreonam, for example: U.S. Pat 4,775,670 and 5,194,604.Aztreonam has polymorph, U.S. Pat 4,826,973 have reported four kinds of different aztreonam crystallizations, promptly α-, β-, γ-, δ-type.Alpha-crystal form is a hydrated crystal, comprises the moisture of 7-15% usually, less stable.Therefore, should convert it into beta crystal, it is anhydrous, nonhygroscopic and have good flowability, less surface-area, better features such as stability that the latter has, and is more suitable for medicinal.
U.S. Pat 4,946,838 have reported the preparation method of beta crystal aztreonam, promptly the alpha-crystal form crystallization are added crystallization in 55～60 ℃ of dehydrated alcohols, alpha-crystal form can temporarily be dissolved in ethanol under these conditions, separates out crystallization then, forms the beta crystal aztreonam.Above-mentioned flow process is not suitable for carrying out sterile production, because aztreonam only keeps the sufficiently long time in solvent, just can carry out sterile filtration.
U.S. Pat 4,946,838 have reported the another kind of method for preparing the beta crystal aztreonam.Alpha-crystal form is dissolved in dehydrated alcohol with the triethylamine salt form, just can obtain the beta crystal aztreonam to wherein adding the anhydrous chlorides of rase hydrogen solution afterwards.Though this method is suitable for carrying out sterile filtration, product is polluted by triethylamine hydrochloride, and the beta crystal aztreonam its related substances that this method obtains is higher.
In U.S. Pat 4,946,838 have reported another kind of production method, at polar aprotic solvent, for example in the second eyeball, add silylating reagent the aztreonam crude product is handled, to obtain the solution of aztreonam silane derivative.Add ethanol in above-mentioned solution, beta crystal promptly is precipitated out.But the productive rate of this method is very low.
Chinese patent CN1545514A discloses a kind of method for preparing aseptic anhydrous beta crystal formation aztreonam, this method is dissolved in dehydrated alcohol with the alpha-crystal form aztreonam under lower temperature, Sterile Filtration then, reheat and stirring obtain solution, the beta crystal aztreonam is separated out from solution, the main drawback of this method is the employed dehydrated alcohol amount of dissolving alpha-crystal form aztreonam very big (60 times), so industrial production efficient is lower.Another shortcoming is that the beta crystal aztreonam that obtains contains ethanol higher (about 2.4%), is not suitable for medicinal.
Purpose of the present invention described below will address these problems exactly.
Summary of the invention
The present invention relates to a kind of new production method, with preparation high purity, the aseptic crystal of anhydrous beta crystal formation aztreonam.
The inventor finds that the alpha-crystal form aztreonam can be dissolved in the mixed solution of dehydrated alcohol and acetone, keeps solution state and do not separate out crystallization in the lower following long period of temperature.The solubleness of alpha-crystal form aztreonam in the mixed solution of dehydrated alcohol and acetone is bigger than the solubleness in dehydrated alcohol.
Utilize the present invention, just no longer need to add triethylamine or silylating reagent when in the mixed solution of dehydrated alcohol and acetone, preparing alpha-crystal form aztreonam solution, the quantity of solvent of using is also fewer, and recrystallize was to generate aseptic beta crystal aztreonam crystal after Pei Zhi solution can carry out sterile filtration like this.
Specifically, the present invention can make the alpha-crystal form aztreonam be dissolved in the mixed solution of dehydrated alcohol and acetone at low temperatures.The alpha-crystal form aztreonam can be dissolved in the mixed solution of dehydrated alcohol and acetone between-10～+ 25 ℃, when temperature is increased to 30～55 ℃, or the stirring by the long period, recrystallize forms the beta crystal crystal.
The alpha-crystal form aztreonam is dissolved in the mixed solution of dehydrated alcohol and acetone and long period and keeps not separating out for Sterile Filtration condition is provided.
If the ethanol content in the beta crystal aztreonam that the solution after filtering obtains during crystallization under lower temperature can be relatively low.
The ratio of mixed solution dehydrated alcohol used in the present invention and acetone can be 6: 1 to 1: 1, and preferred ratio is 4: 1 to 2: 1, and preferred ratio is 3: 1 to 2: 1.
The amount that alpha-crystal form dehydrated alcohol that aztreonam uses and acetone mixed solution are dissolved in the present invention can be 12 times to 60 times, and preferred quantity of solvent is 18 times to 30 times, and more excellent quantity of solvent is 20 to 25 times.When quantity of solvent very little the time dissolving of alpha-crystal form aztreonam not exclusively, and solution generates the crystallization of beta crystal aztreonam easily before filtration.If quantity of solvent is too many, production efficiency can reduce.
Above-mentioned alpha-crystal form aztreonam solution is sloughed color after can be by carbon treatment, also can carry out Sterile Filtration by sterilizing filter.
The alpha-crystal form aztreonam is dissolved in dehydrated alcohol, and temperature range is-10～+ 25 ℃, and optimum temps is 5～15 ℃, if solvent temperature is crossed the higher position aztreonam is separated out before filtration.Solution is kept said temperature, filter sterile solution with activated carbon treatment after-filtration and sterile filters respectively.Afterwards, the temperature of aseptic filtrate is risen to 30～55 ℃ or stirring by the long period, will form the crystallization of anhydrous beta crystal formation aztreonam.Above-mentioned product also need be through filtering and drying.
Beta crystal aztreonam by the inventive method preparation is suitable for medicinal, for example with after the L-arginine mixes, and can be by intravenous injection and muscle injection mode medication.
Compared with former technology, major advantage of the present invention is to simplify production process, enhance productivity, and can be by the ethanol content in the method realization reduction product beta crystal aztreonam such as reduction Tc.
The used alpha-crystal form aztreonam of the present invention can be used known method, as Chinese patent CN1, and 681,812, U.S. Pat 5,194, methods such as 604 preparation, or on market, buy, beta crystal aztreonam standard substance are by the preparation of U.S. Pat 4,946,838 methods.
Embodiment
Following non-limiting example will further specify the present invention.Wherein measuring the residual GC conditions of ethanol is: with poly-di-alcohol (SUPELCOWAX-10) is stationary phase 30m * 0.32mm * 0.5 μ m, with the flame ionization ditector is detector, heating schedule: 50 ℃ (constant temperature 6min), temperature rise rate with 15 ℃/min rises to 100 ℃, rise to 180 ℃ (constant temperature 10min) with 30 ℃/min temperature rise rate again, pressure program: 28kPa (9min), with the speed of 10kPa/min to 55kPa (10min), injector temperature: 90 ℃; Detector temperature: 230 ℃, flow rate of carrier gas: 0.8ml/min (nitrogen); Splitting ratio 1: 10.Accurate ethanol is an amount of, is mixed with the solution of ethanol 2000 μ g/ml, product solution in contrast with methyl-sulphoxide as solvent.Get the about 0.1g of this product, the accurate title, decide, in the top set empty bottle, and the accurate methyl-sulphoxide 1ml that adds, jolting makes dissolving, as need testing solution; Precision is measured need testing solution and each 1 μ l of reference substance solution, and inject gas chromatograph writes down color atlas respectively.Press external standard method with calculated by peak area.The ratio of ethanol and acetone is by volume calculated among the embodiment.
Reference example 1
Under 8～10 ℃, with in the dehydrated alcohol of alpha-crystal form aztreonam (40g) adding precooling (2400ml), stir and obtained clear solution in 30 minutes, keep 8～10 ℃, add activated carbon (1g) and stirred above-mentioned solution 15 minutes, the gained suspension filtered, filter cake washs with ethanol (50ml), afterwards, filtrate slowly was heated to 50～55 ℃ under stirring in 2 hours, and separating out crystallization is the beta crystal aztreonam, suspension is cooled to 15～20 ℃, stirred 1 hour and filtered once more, the vacuum-drying of gained crystallized product obtains the 28g product.Infared spectrum shows that with powder x-ray diffraction product is consistent with standard substance (beta crystal aztreonam) crystalline form.The gas chromatographic analysis ethanol content is 2.3%.
Embodiment 1
Under 10～15 ℃, alpha-crystal form aztreonam (40g) is added the dehydrated alcohol and the acetone of precooling
(3: 1)Mixed solution in (1000ml), stir and obtained clear solution in 5 minutes, keep 10～15 ℃, add activated carbon (1g) and stirred above-mentioned solution 15 minutes, the gained suspension filtered, filter cake is with acetone (50ml) washing, afterwards, filtrate slowly was heated to 35～40 ℃ under stirring in 2 hours, and separating out crystallization is the beta crystal aztreonam.Suspension is cooled to 15～20 ℃, stirred 1 hour and filtered once more, the vacuum-drying of gained crystallized product obtains the 33.5g product.Infared spectrum shows that with powder x-ray diffraction product is consistent with standard substance (beta crystal aztreonam) crystalline form.The gas chromatographic analysis ethanol content is 0.9%.
Embodiment 2
Under 10～15 ℃, alpha-crystal form aztreonam (40g) is added the dehydrated alcohol and the acetone of precooling
(3: 1)Mixed solution in (1000ml), stir and obtained clear solution in 5 minutes, keep 10～15 ℃, add activated carbon (1g) and stirred above-mentioned solution 15 minutes, the gained suspension filtered, filter cake washs with acetone (50ml), the filtrate vigorous stirring is begun the adularescent crystallization after 40 minutes separate out, continuing to stir had mass crystallization to separate out in 1 hour, in 30 minutes solution slowly is heated to 35～40 ℃ under stirring crystallization is separated out fully, and separating out crystallization is the beta crystal aztreonam.Suspension is cooled to 15～20 ℃, stirred 1 hour and filtered once more, the vacuum-drying of gained crystallized product obtains the 32g product.The gas chromatographic analysis ethanol content is 0.4%.
Claims (10)
1. the method for preparing anhydrous beta crystal formation aztreonam, be included under-10～+ 25 ℃ the temperature, the alpha-crystal form aztreonam is dissolved in the mixed solution of 12 times to 60 times 6: 1 to 1: 1 dehydrated alcohols and acetone, through after the Sterile Filtration, solution is heated to 30～55 ℃ again, to form the crystallization of anhydrous beta crystal formation aztreonam.
2. the method for preparing anhydrous beta crystal formation aztreonam, comprise: under-10～+ 25 ℃ temperature, the alpha-crystal form aztreonam is dissolved in the mixed solution of 12 times to 60 times 6: 1 to 1: 1 dehydrated alcohols and acetone, through after the Sterile Filtration, again with the solution vigorous stirring, to form the crystallization of anhydrous beta crystal formation aztreonam.
3. the method for preparing aztreonam solution comprises the mixed solution that the alpha-crystal form aztreonam is dissolved in 12 times to 60 times 6: 1 to 1: 1 dehydrated alcohols and acetone.
4. the method for claims 1, the temperature range of wherein dissolving the alpha-crystal form aztreonam is 5～15 ℃.
5. the method for claims 1, wherein the ratio of dehydrated alcohol and acetone is 4: 1 to 2: 1, the amount of dehydrated alcohol and acetone mixed solution is 18 times to 30 times.
6. the method for claims 1, wherein the ratio of dehydrated alcohol and acetone is 3: 1 to 2: 1, the amount of dehydrated alcohol and acetone mixed solution is 20 times to 25 times.
7. the method for claims 2, the temperature range of wherein dissolving the alpha-crystal form aztreonam is 5～15 ℃.
8. the method for claims 2, wherein the ratio of dehydrated alcohol and acetone is 4: 1 to 2: 1, the amount of dehydrated alcohol and acetone mixed solution is 18 times to 30 times
9. the method for claims 2, wherein the ratio of dehydrated alcohol and acetone is 3: 1 to 2: 1, the amount of dehydrated alcohol and acetone mixed solution is 20 times to 25 times.
10. the method for claims 3, the temperature range of wherein dissolving the alpha-crystal form aztreonam is-10～+ 25 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CNA2006101610715A CN101195618A (en) | 2006-12-05 | 2006-12-05 | Method for producing beta crystal system anhydrous aztreonam |
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| CNA2006101610715A CN101195618A (en) | 2006-12-05 | 2006-12-05 | Method for producing beta crystal system anhydrous aztreonam |
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| CN101195618A true CN101195618A (en) | 2008-06-11 |
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| CNA2006101610715A Pending CN101195618A (en) | 2006-12-05 | 2006-12-05 | Method for producing beta crystal system anhydrous aztreonam |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102351855A (en) * | 2011-08-12 | 2012-02-15 | 山西仟源制药股份有限公司 | Production method of beta-crystal form aztreonam aseptic raw drug |
| CN105055407A (en) * | 2015-09-15 | 2015-11-18 | 青岛华之草医药科技有限公司 | Medicine aztreonam composition for curing infectious diseases |
-
2006
- 2006-12-05 CN CNA2006101610715A patent/CN101195618A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102351855A (en) * | 2011-08-12 | 2012-02-15 | 山西仟源制药股份有限公司 | Production method of beta-crystal form aztreonam aseptic raw drug |
| CN105055407A (en) * | 2015-09-15 | 2015-11-18 | 青岛华之草医药科技有限公司 | Medicine aztreonam composition for curing infectious diseases |
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Open date: 20080611 |