CN1544440A - Novel pulveres fosfomycin trometamol synthetic method - Google Patents
Novel pulveres fosfomycin trometamol synthetic method Download PDFInfo
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- CN1544440A CN1544440A CNA2003101052081A CN200310105208A CN1544440A CN 1544440 A CN1544440 A CN 1544440A CN A2003101052081 A CNA2003101052081 A CN A2003101052081A CN 200310105208 A CN200310105208 A CN 200310105208A CN 1544440 A CN1544440 A CN 1544440A
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- fosfomycin
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- tromethamine
- phosphonomycin
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Abstract
The invention provides a process for synthesizing pulveres fosfomycin trometamol by using phosphonomycin sodium or neutral phosphonomycin sodium containing small amount of organic acid as raw material through the steps of, subjecting 10-16 times of type H cationic ion-exchange resin to exchange reaction in methanol solution at low-temperature, with the methanol solution acting as eluent, thus preparing the methanol solution containing fosfomycin acid, neutralizing the methanol solution with right amount of tromethamine or fosfomycin methanol tromethamine salt so as to obtain the methanol solution of pulveres fosfomycin trometamol, and the end product of the methanol solution of pulveres fosfomycin trometamol is obtained from the methanol solution of pulveres fosfomycin trometamol from decolorizing, filtering, condensing, extracting, filtering and drying.
Description
One, technical field:
The invention provides a kind ofly with fosfomycin sodium or to contain a small amount of organic acid Sodium fosfomycin be raw material, the method for synthetic pulveres fosfomycin tromethamine belongs to the synthetic field of fine chemistry industry.
Two, background technology:
Phosphonomycin is a kind of wide spectrum, low toxicity, is difficult for sensitization, is difficult for producing resistance, has synergistic a kind of antibiotic with most of antibiotic, it is the metabolite that isolated streptomyces fradiae produces through cultivation from Spain's soil in 1966, and gram-positive microorganism and Gram-negative bacteria are all had inhibition and killing action.Phosphonomycin exists with calcium salt and sodium-salt form usually, and calcium salt is used for oral, and sodium salt is used for intravenous injection or drop.Sodium salt divides Sodium fosfomycin and alkaline fosfomycin sodium again.In the production process of fosfomycin sodium and Sodium fosfomycin, owing to some reasons, can produce some unacceptable products, it is defective mainly to show as aseptic, thermal source, glycol (content＞0.5%) etc., for doing over again of these unacceptable products, have aseptic as alkaline fosfomycin sodium, thermal source is defective, can take simple water means re-crystallization to make with extra care; And have to show as glycol as fosfomycin sodium (alkalescence, neutrality) defective or Sodium fosfomycin is aseptic, thermal source etc. is defective, wherein glycol content is high, take the mode of water recrystallization effectively glycol content not to be lowered, the Sodium fosfomycin water carries out recrystallizing and refining simultaneously, organic acid wherein can with fosfomycin sodium generation neutralization reaction, generate the mixture of more complicated.Therefore, take the mode of water recrystallization to be not suitable for for doing over again of these unacceptable products.In order to address this problem, we have found a kind of with fosfomycin sodium or to contain a small amount of organic acid Sodium fosfomycin be raw material, the novel method of synthetic pulveres fosfomycin tromethamine, in production application, this method can be used for solving doing over again of defective fosfomycin sodium (alkalescence, neutrality) and utilizes problem again.
Pulveres fosfomycin tromethamine salt, chemistry is by name: single (2-amino-2-methylol-1, ammediol) (2R-cis) (3-methyl isophthalic acid, 2-epoxypropyl) phosphoric acid salt, its chemical structure skeleton symbol is:
Pulveres fosfomycin tromethamine salt is the earliest by the invention of Italian Zambon company, and this salt has characteristics such as good water solubility, oral absorption are fast, bioavailability height, and being used for the treatment of urinary system infection in the clinical application has good result.Pulveres fosfomycin tromethamine salt is extensive use of in states such as America and Europes as a kind of choice drug for the treatment of urinary system infection at present.
The synthetic method of pulveres fosfomycin tromethamine salt mainly contains two kinds:
1, be raw material with phosphonomycin dextrorotation phenylethylamine salt (being called for short left salt), Trometamol with 2 times of molar weights in ethanolic soln reacts, generate the two tromethamine salts (GB.2025975) of phosphonomycin, this pair salt reacts with tosic acid in dehydrated alcohol, makes pulveres fosfomycin tromethamine salt (EP.27579; GB.2062640), through ethanol refining pure product pulveres fosfomycin tromethamine salt (synthetic method of Italian Zambon company report).
2, be raw material with left salt, in methanol solution, in low temperature down and H type Zeo-karb carry out permutoid reaction, obtain phosphonomycin acid, this acid is carried out neutralization reaction with Trometamol, promptly obtain pulveres fosfomycin tromethamine salt finished product (CA:117,251557r, CN 911063005, the synthetic method of Dongbei Pharmaceutical General Factory report).
Three, summary of the invention:
Goal of the invention: the purpose of this invention is to provide a kind of is raw material with the fosfomycin sodium, the method for preparing pulveres fosfomycin tromethamine salt is mainly used in the problem that aspect such as processing that the defective fosfomycin sodium that produces in the fosfomycin sodium production and defective Sodium fosfomycin done over again exists.
Technical scheme: the object of the present invention is achieved like this:
Its operation steps is as follows:
1, will be that the fosfomycin sodium of unit carries out permutoid reaction with the H type Zeo-karb that is 10～16 times of amounts of unit with the gram with the milliliter in methanol solution under low temperature in post, methanol solution be made eluent, can contain the methanol solution of phosphonomycin acid;
2,, obtain the methanol solution of pulveres fosfomycin tromethamine with the methanol solution that contains phosphonomycin acid in appropriate amounts of ammonia trihydroxybutane or the two tromethamine salt neutralization procedures 1 of phosphonomycin;
3, the methanol solution with the pulveres fosfomycin tromethamine in the step 2 adds activated carbon decolorizing, filters, is concentrated into certain volume, add and to contain the above Fatty Alcohol(C12-C14 and C12-C18) of two carbon atoms or ketone organic solvent crystallization, filtration, drying, the pulveres fosfomycin tromethamine salt finished product; Wherein: a, fosfomycin sodium glycol content≤1.0%; B, fosfomycin sodium g: Trometamol g: methyl alcohol ml=1: 0.57～0.598: 41.3～45.8; Or fosfomycin sodium g: two Trometamol g: the methyl alcohol ml=1: 1.79～1.935: 41.4～44.8 of phosphonomycin.
The crystallization solvent can be selected dehydrated alcohol, Virahol or acetone for use in step 3.
In phosphonomycin acid is carried out with Trometamol and the time, after step 3 concentrates, it is 2.7～3.6 times of fosfomycin sodium charging capacity of unit that the liquid volume ml vol should be controlled at the gram, crystallization with the solvent ml vol for the gram being 5.5～5.6 times of fosfomycin sodium charging capacity of unit; In phosphonomycin acid is carried out with phosphonomycin pair tromethamine salts and the time, it is 3.4～4.2 times of unit fosfomycin sodium charging capacity that the volume ml vol that step 3 concentrates back liquid should be controlled at the gram, and crystallization is to be 11～12 times of unit fosfomycin sodium charging capacity with the gram with the solvent ml vol.
Step 1 exchange Controllable Temperature is built in-20～-10 ℃.
With the fosfomycin sodium is starting raw material, or to contain a small amount of organic acid Sodium fosfomycin be raw material, or the fosfomycin sodium of the phosphorus of alkalescence.
Concrete reaction process is:
The acid of Zeo-karb phosphonomycin
Pulveres fosfomycin tromethamine
Or
The two tromethamine salts of phosphonomycin
Advantage and effect: adopting provided by the invention is the synthetic pulveres fosfomycin tromethamine novel method of raw material with fosfomycin sodium (neutral, alkalescence), can solve in neutrality or the alkaline fosfomycin sodium production process doing over again of unacceptable product effectively and utilize problem again, having overcome conventional process for purification can not be with underproof fosfomycin sodium of glycol (alkalescence, neutrality) or deficiency aseptic, that the underproof Sodium fosfomycin of thermal source is done over again and existed.Defective fosfomycin sodium (neutral, alkalescence) is changed into pulveres fosfomycin tromethamine, and its yield is consistent with the yield of background technology CN911063005 report.In addition, in the methods of the invention, in phosphonomycin acid is carried out with phosphonomycin pair tromethamine salts and the time, can obtain the normal pulveres fosfomycin tromethamine salt of twice, single batch of output has increased by one times, has improved equipment capacity.
Four, embodiment:, recommend following most preferred embodiment in order to understand the present invention better;
Embodiment 1:
Measure the 70ml anhydrous methanol and join in the beaker that fills 170ml exsiccant D001 type Zeo-karb, stir, then resin is joined together with methyl alcohol in the exchange column that has interlayer, open the low temperature bath, column temperature is reduced to-20 ℃.The methyl alcohol liquid level is just a little more than the resin face in the adjustment post, then 14.5g fosfomycin sodium (glycol is 0.65%) is joined and begin permutoid reaction in the exchange column, make eluent with anhydrous methanol, continuous wash-out, till the post bottom no longer includes phosphonomycin acid outflow, approximately use anhydrous methanol 600ml, the phosphonomycin acid methanol solution that elutes is directly joined in the 1000ml four-hole bottle that fills the 8.6g Trometamol, carry out neutralization reaction, add small amount of activated decolouring 10 minutes then, filter, be evaporated to liquid volume 40～50ml, add 80ml dehydrated alcohol crystallization.Filter, filter cake is with 20ml absolute ethanol washing twice, drying, pulveres fosfomycin tromethamine finished product 16.7g, m.p:117～120 ℃.
Embodiment 2:
Measure the 100ml anhydrous methanol and join in the beaker that fills 220ml exsiccant D001 type Zeo-karb, stir, then resin is joined together with methyl alcohol in the exchange column that has interlayer, open the low temperature bath, column temperature is reduced to-17 ℃.The methyl alcohol liquid level is just a little more than the resin face in the adjustment post, then the 14.5g Sodium fosfomycin is joined and begin permutoid reaction in the exchange column, make eluent with anhydrous methanol, continuous wash-out, till the post bottom no longer includes phosphonomycin acid outflow, approximately use anhydrous methanol 650ml, the phosphonomycin acid methanol solution that elutes is directly joined in the 1000ml four-hole bottle that fills the two tromethamine salts of 26.0g phosphonomycin, carry out neutralization reaction, add small amount of activated decolouring 10 minutes then, filter, be evaporated to liquid volume 50～60ml, add 160ml dehydrated alcohol crystallization.Filter, filter cake 30ml absolute ethanol washing twice, drying obtains pulveres fosfomycin tromethamine finished product 33.2g.
The method for making of the two tromethamine salts of attached phosphonomycin:
Take by weighing the 31g Trometamol and join in the 500ml four-hole bottle, add the 380ml dehydrated alcohol, heating, stirring make it dissolving.After the dissolving, be cooled to 75 ℃, add phosphonomycin dextrorotation phenylethylamine salt 32g, be incubated 1.5 hours down at 75 ℃, be cooled to 10 ℃ then, filter, filter cake washs at twice with the 40ml dehydrated alcohol, and filter is done, drying, the two tromethamine salt finished product 41g of phosphonomycin, m.p:142～144 ℃.
Embodiment 3:
Measure the 50ml anhydrous methanol and join in the beaker that fills 150ml exsiccant D001 type Zeo-karb, stir, then resin is joined together with methyl alcohol in the exchange column that has interlayer, open the low temperature bath, column temperature is reduced to-14 ℃.The methyl alcohol liquid level is just a little more than the resin face in the adjustment post, then 14.5g fosfomycin sodium (glycol is 1.0%) is joined and begin permutoid reaction in the exchange column, make eluent with anhydrous methanol, continuous wash-out, till the post bottom no longer includes phosphonomycin acid outflow, approximately use anhydrous methanol 600ml, the phosphonomycin acid methanol solution that elutes is directly joined in the 1000ml four-hole bottle that fills the two tromethamine salts of 28g phosphonomycin, carry out neutralization reaction, add small amount of activated decolouring 10 minutes then, filter, be evaporated to liquid volume 50～60ml, add 160ml anhydrous propanone crystallization.Filter, filter cake 30ml anhydrous propanone washed twice, drying obtains pulveres fosfomycin tromethamine finished product 33.5g.；
Embodiment 4:
Measure the 80ml anhydrous methanol and join in the beaker that fills 200ml exsiccant D001 type Zeo-karb, stir, then resin is joined together with methyl alcohol in the exchange column that has interlayer, open the low temperature bath, column temperature is reduced to-10 ℃.The methyl alcohol liquid level is just a little more than the resin face in the adjustment post, then the 14.5g Sodium fosfomycin is joined and begin permutoid reaction in the exchange column, make eluent with anhydrous methanol, continuous wash-out, till the post bottom no longer includes phosphonomycin acid outflow, approximately use anhydrous methanol 650ml, the phosphonomycin acid methanol solution that elutes is directly joined in the 1000ml four-hole bottle that fills the 8.3g Trometamol, carry out neutralization reaction, add small amount of activated decolouring 10 minutes then, filter, be evaporated to liquid volume 40～50ml, add 80ml anhydrous isopropyl alcohol crystallization.Filter, filter cake 20ml anhydrous isopropyl alcohol washed twice, drying promptly obtains pulveres fosfomycin tromethamine finished product 16.5g.
With the fosfomycin sodium is starting raw material, or to contain a small amount of organic acid Sodium fosfomycin be raw material, and it can select salable product for use, also can select for use aseptic, thermal source, glycol etc. to detect unacceptable product, fosfomycin sodium can be selected neutral for use, also can select alkalescence for use.
Claims (5)
1, a kind of pulveres fosfomycin tromethamine new synthetic method, it is characterized in that: the operation steps of this method is as follows:
(1), will be the fosfomycin sodium of unit with the gram and the H type Zeo-karb that is 10～16 times of amounts of unit carries out permutoid reaction with the milliliter in methanol solution under low temperature in post, methanol solution is made eluent, can contain the methanol solution of phosphonomycin acid;
(2), with the methanol solution that contains phosphonomycin acid in the two tromethamine salt neutralization procedures 1 of appropriate amounts of ammonia trihydroxybutane or phosphonomycin, obtain the methanol solution of pulveres fosfomycin tromethamine;
(3), the methanol solution with the pulveres fosfomycin tromethamine in the step 2 adds activated carbon decolorizing, filters, is concentrated into certain volume, add and to contain the above Fatty Alcohol(C12-C14 and C12-C18) of two carbon atoms or ketone organic solvent crystallization, filtration, drying, the pulveres fosfomycin tromethamine salt finished product; Wherein: a, fosfomycin sodium glycol content≤1.0%; B, fosfomycin sodium g: Trometamol g: methyl alcohol ml=1: 0.57～0.598: 41.3～45.8; Or fosfomycin sodium g: two Trometamol g: the methyl alcohol ml=1: 1.79～1.935: 41.4～44.8 of phosphonomycin.
2, pulveres fosfomycin tromethamine new synthetic method according to claim 1, it is characterized in that: the crystallization solvent can be selected dehydrated alcohol, Virahol or acetone for use in step 3.
3, pulveres fosfomycin tromethamine new synthetic method according to claim 1, it is characterized in that: in phosphonomycin acid is carried out with Trometamol and the time, after step 3 concentrates, it is 2.7～3.6 times of fosfomycin sodium charging capacity of unit that the liquid volume ml vol should be controlled at the gram, crystallization with the solvent ml vol for the gram being 5.5～5.6 times of fosfomycin sodium charging capacity of unit; In phosphonomycin acid is carried out with phosphonomycin pair tromethamine salts and the time, it is 3.4～4.2 times of unit fosfomycin sodium charging capacity that the volume ml vol that step 3 concentrates back liquid should be controlled at the gram, and crystallization is to be 11～12 times of unit fosfomycin sodium charging capacity with the gram with the solvent ml vol.
4, pulveres fosfomycin tromethamine new synthetic method according to claim 1 is characterized in that: step 1 exchange Controllable Temperature is built in-20～-10 ℃.
5, pulveres fosfomycin tromethamine new synthetic method according to claim 1 is characterized in that: be starting raw material with the fosfomycin sodium, or to contain a small amount of organic acid Sodium fosfomycin be raw material, or the fosfomycin sodium of the phosphorus of alkalescence.
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| CN 200310105208 CN1264852C (en) | 2003-11-27 | 2003-11-27 | Novel pulveres fosfomycin trometamol synthetic method |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1762573A1 (en) * | 2005-09-08 | 2007-03-14 | Interquim, S.A. De C.V. | A process for the preparation of fosfomycin salts |
| CN101845059A (en) * | 2010-06-08 | 2010-09-29 | 张庆武 | New method for preparing fosfomycin sodium for injection |
| CN101928300B (en) * | 2009-10-19 | 2011-09-14 | 湖北迅达药业股份有限公司 | New preparation method of pulveres fosfomycin tromethamine salt |
| CN102351902A (en) * | 2011-08-12 | 2012-02-15 | 山西仟源制药股份有限公司 | Preparation method of fosfomycin monoamine butantriol |
| CN102659842A (en) * | 2012-04-18 | 2012-09-12 | 安徽赛诺医药化工有限公司 | New method for synthesizing fosfomycin trometamol |
| CN102807586A (en) * | 2012-08-31 | 2012-12-05 | 东北制药（沈阳）科技发展有限公司 | Preparation method of fosfomycin amine salt |
-
2003
- 2003-11-27 CN CN 200310105208 patent/CN1264852C/en not_active Expired - Fee Related
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1762573A1 (en) * | 2005-09-08 | 2007-03-14 | Interquim, S.A. De C.V. | A process for the preparation of fosfomycin salts |
| CN101928300B (en) * | 2009-10-19 | 2011-09-14 | 湖北迅达药业股份有限公司 | New preparation method of pulveres fosfomycin tromethamine salt |
| CN101845059A (en) * | 2010-06-08 | 2010-09-29 | 张庆武 | New method for preparing fosfomycin sodium for injection |
| CN101845059B (en) * | 2010-06-08 | 2013-01-23 | 东北制药集团股份有限公司 | New method for preparing fosfomycin sodium for injection |
| CN102351902A (en) * | 2011-08-12 | 2012-02-15 | 山西仟源制药股份有限公司 | Preparation method of fosfomycin monoamine butantriol |
| CN102659842A (en) * | 2012-04-18 | 2012-09-12 | 安徽赛诺医药化工有限公司 | New method for synthesizing fosfomycin trometamol |
| CN102807586A (en) * | 2012-08-31 | 2012-12-05 | 东北制药（沈阳）科技发展有限公司 | Preparation method of fosfomycin amine salt |
| WO2014032363A1 (en) | 2012-08-31 | 2014-03-06 | 东北制药（沈阳）科技发展有限公司 | Method for preparing fosfomycin ammonium salt |
| CN102807586B (en) * | 2012-08-31 | 2015-05-13 | 东北制药集团股份有限公司 | Preparation method of fosfomycin amine salt |
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| CN1264852C (en) | 2006-07-19 |
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