CN102351902A - Preparation method of fosfomycin monoamine butantriol - Google Patents
Preparation method of fosfomycin monoamine butantriol Download PDFInfo
- Publication number
- CN102351902A CN102351902A CN2011102311891A CN201110231189A CN102351902A CN 102351902 A CN102351902 A CN 102351902A CN 2011102311891 A CN2011102311891 A CN 2011102311891A CN 201110231189 A CN201110231189 A CN 201110231189A CN 102351902 A CN102351902 A CN 102351902A
- Authority
- CN
- China
- Prior art keywords
- acid
- phosphonomycin
- fosfomycin
- organic solvent
- methyl alcohol
- 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
Abstract
The invention provides a preparation method of fosfomycin monoamine butantriol. The method comprises the following steps of: adding fosfomycin diamine butantriol salt into methanol, adding acid to adjust the pH to be between 4 and 7 at the temperature of between 5 DEG C below zero and 30 DEG C, filtering, removing filter residue, adding an organic solvent into the filtrate to separate out crystal, filtering, drying, and thus obtaining a fosfomycin monoamine butantriol finished product. The method is simple in reaction, the yield can reach 85 to 90 percent, the product content (the detection content can reach over 99 percent) is high, and the method is suitable for industrialized production and has great application value.
Description
Technical field
The present invention relates to pharmaceutical chemistry, be specifically related to a kind of preparation method of pulveres fosfomycin tromethamine.
Background technology
Pulveres fosfomycin tromethamine, its chemical name: single (2-amino-2-methylol-1, ammediol) (2R-cis) (3-methyl isophthalic acid, 2-epoxypropyl) phosphoric acid salt, chemical structural formula is:
Pulveres fosfomycin tromethamine salt is by the invention in 1981 of Italian Zambon company; This salt has characteristics such as good water solubility, oral absorption are fast, bioavailability height; These article belong to Tri-Biocin; Molecular structure is similar with phosphoenolpyruvic acid; So can compete same transferring enzyme; Make the early stage biosynthesis block of bacteria cell wall, and cause thalline to break, bacterial death.These article and microbiotic such as penicillins, cephalosporins, aminoglycosides are synergy strengthening effect and suspension of pesticide resistance generation when share.Be used for the pathogenic bacterium caused lower urinary tract infection responsive, like urocystitis, urethritis to these article.
At present, the pulveres fosfomycin tromethamine salt preparation method of existing bibliographical information mainly contains following several:
1, the synthesis method of Italian Zambon company: with fosfomycin phenylethylamine salt is raw material, in ethanol, with bimolecular Trometamol reaction, generates the two tromethamine salt (GB2025975 of phosphonomycin; Spam ES577527), this salt reacts with tosic acid (patent comprises other sulfonic acid class, and alkylsulphonic acid, aryl sulfonic acid, sweet-smelling alkyl sulfonic acid are arranged) in dehydrated alcohol, makes pulveres fosfomycin tromethamine (EP.27579; GB.2062640).
2, with the Fosmicin be raw material, add Trometamol and oxalic acid, single step reaction makes pulveres fosfomycin tromethamine (CN90106290.1, Chinese Medicine Industry Inst., Shandong Prov.).
3, be raw material with fosfomycin phenylethylamine salt, in methyl alcohol, in low temperature down and hydrogen type cation exchange resin react; Get phosphonomycin acid; In this acid, add Trometamol and carry out neutralization reaction, get pulveres fosfomycin tromethamine salt finished product (CN91106300.5, Northeast China pharmacy head factory).
4, with the fosfomycin sodium be raw material; With H type Zeo-karb in methanol solution; In in post, carrying out permutoid reaction under the low temperature; After obtaining phosphonomycin acid; With an amount of Trometamol or the two tromethamine salt neutralizations of phosphonomycin; Get pulveres fosfomycin tromethamine salt finished product (CN200310105208.1, Northeast China pharmacy head factory).
But aforesaid method comes with some shortcomings: as: the sulfonic acid tromethamine salt reclaims difficulty, and Fosmicin is poorly soluble in water and organic solvent, and reaction is incomplete, and the intermediate phosphonomycin that generates acid is unstable, facile hydrolysis etc.Therefore, need address these problems aborning.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, and the research and design method is easy, the industrialized preparing process that yield is high.
The invention provides a kind of preparation method of pulveres fosfomycin tromethamine.
The inventive method is added to the two tromethamine salts of phosphonomycin in the methyl alcohol; Under the temperature of-5 ℃ to 30 ℃ (preferred 15～25 ℃ more preferably 20～25 ℃); Add mineral acid or organic acid again; Regulating PH is 4～7; Add after-filtration; Remove filter residue (being mainly Trometamol and sour salt), add organic solvent crystallization, filtration, drying (putting into 40 ℃ of freeze-day with constant temperature of baking oven) in the filtrating, get the pulveres fosfomycin tromethamine finished product.
The two Trometamols (g) of the said phosphonomycin of the inventive method: methyl alcohol (ml): crystallization organic solvent (ml): consumption be 1: 5.5～20: 11.0～40.0.(preferred 1: 6～10: 11～20; More preferably 1: 6: 12)
Described mineral acid of the inventive method or organic acid are like sulfuric acid, phosphoric acid, trifluoroacetic acid or trichoroacetic acid(TCA).
The organic solvent that said crystallization is used comprises one or more mixed solvents such as ethanol, propyl alcohol, Virahol, butanols, methyl-formiate, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butylacetate, acetone or butanone.
The inventive method has overcome the defective that prior art exists, and reaction is simple, and yield can reach 85～90%, and product content high (can reach more than 99% with liquid phase HPLC detection level) is suitable for suitability for industrialized production, and bigger using value is arranged.
Embodiment
Embodiment 1
Add anhydrous methanol 480ml in the reaction flask, stir the two tromethamine salts of adding 80g phosphonomycin down, temperature control is at 20 ℃; Add sulfuric acid and transfer PH to 6.7; Stir half an hour, filter, add ethyl acetate 1000ml in the filtrating; Appearance back insulation to be crystallized (20 ℃ of temperature) was stirred 2 hours; Filter,, drain after drying (putting into 40 ℃ of freeze-day with constant temperature of baking oven) with ethyl acetate 10ml washing; Get pulveres fosfomycin tromethamine 47.5g, yield: 87.0%.It is 99.5% that liquid phase HPLC detects pulveres fosfomycin tromethamine content.
Embodiment 2
Add anhydrous methanol 500ml in the reaction flask, stir the two tromethamine salts of adding 80g phosphonomycin down, temperature control is at 15 ℃; Add trichoroacetic acid(TCA) and transfer PH to 6.2; Stir half an hour, filter, add methyl acetate 1200ml in the filtrating; Appearance back insulation to be crystallized (20 ℃ of temperature) was stirred 2 hours; Filter,, drain after drying (putting into 40 ℃ of freeze-day with constant temperature of baking oven) with methyl acetate 10ml washing; Get pulveres fosfomycin tromethamine 47.1g, yield: 86.3%.Detecting pulveres fosfomycin tromethamine content is 99.0%.
Claims (9)
1. the preparation method of pulveres fosfomycin tromethamine is characterized in that, this method is:
The two tromethamine salts of phosphonomycin are added in the methyl alcohol, under-5 ℃ to 30 ℃ temperature, add mineral acid or organic acid again; Regulating PH is 4～7; Add after-filtration, remove filter residue, add organic solvent crystallization, filtration, the dry pulveres fosfomycin tromethamine finished product that gets in the filtrating.
2. according to the method for claim 1, it is characterized in that, said the two tromethamine salts of phosphonomycin are added in the methyl alcohol, under 15～25 ℃ temperature, add mineral acid or organic acid again.
3. according to the method for claim 2, it is characterized in that, said the two tromethamine salts of phosphonomycin are added in the methyl alcohol, under 20～25 ℃ temperature, add mineral acid or organic acid again.
4. according to the method for claim 1, it is characterized in that the two Trometamol g of said phosphonomycin: methyl alcohol ml: crystallization organic solvent ml: consumption be 1: 5.5～20: 11.0～40.0.
5. according to the method for claim 4, it is characterized in that the two Trometamol g of said phosphonomycin: methyl alcohol ml: crystallization organic solvent ml: consumption be 1: 6～10: 11～20.
6. according to the method for claim 5, it is characterized in that the two Trometamol g of said phosphonomycin: methyl alcohol ml: crystallization organic solvent ml: consumption be 1: 6: 12.
7. according to the method for claim 1, it is characterized in that said mineral acid or organic acid are sulfuric acid, phosphoric acid, trifluoroacetic acid or trichoroacetic acid(TCA).
8. according to each method among the claim 1-3; It is characterized in that the said organic solvent of analysing is one or more mixed solvents in ethanol, propyl alcohol, Virahol, butanols, methyl-formiate, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butylacetate, acetone or the butanone.
9. according to the method for claim 1, it is characterized in that drying temperature is 40 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011102311891A CN102351902A (en) | 2011-08-12 | 2011-08-12 | Preparation method of fosfomycin monoamine butantriol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011102311891A CN102351902A (en) | 2011-08-12 | 2011-08-12 | Preparation method of fosfomycin monoamine butantriol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102351902A true CN102351902A (en) | 2012-02-15 |
Family
ID=45575568
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011102311891A Pending CN102351902A (en) | 2011-08-12 | 2011-08-12 | Preparation method of fosfomycin monoamine butantriol |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102351902A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN108997424A (en) * | 2017-06-06 | 2018-12-14 | 湖南华纳大药厂手性药物有限公司 | A kind of simple and direct method for preparing fosfomycin trometamol |
| CN108997425A (en) * | 2017-06-06 | 2018-12-14 | 湖南华纳大药厂手性药物有限公司 | A method of preparing high-content fosfomycin trometamol |
| WO2020147160A1 (en) * | 2019-01-18 | 2020-07-23 | 科大华采(武汉)生物科技股份有限公司 | Method for preparing fosfomycin trometamol |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2062640A (en) * | 1979-10-18 | 1981-05-28 | Zambon Spa | Fosfomycin salt |
| US5162309A (en) * | 1989-07-27 | 1992-11-10 | Zambon Group | Mono (2-ammonium-2-hydroxymethyl-1,3-propanediol)(2r,cis)-1,2-ep-oxipropyl-phosphonate with improved characteristics of stability and processing |
| CN1544440A (en) * | 2003-11-27 | 2004-11-10 | 东北制药总厂 | Novel pulveres fosfomycin trometamol synthetic method |
-
2011
- 2011-08-12 CN CN2011102311891A patent/CN102351902A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2062640A (en) * | 1979-10-18 | 1981-05-28 | Zambon Spa | Fosfomycin salt |
| US5162309A (en) * | 1989-07-27 | 1992-11-10 | Zambon Group | Mono (2-ammonium-2-hydroxymethyl-1,3-propanediol)(2r,cis)-1,2-ep-oxipropyl-phosphonate with improved characteristics of stability and processing |
| CN1544440A (en) * | 2003-11-27 | 2004-11-10 | 东北制药总厂 | Novel pulveres fosfomycin trometamol synthetic method |
Non-Patent Citations (1)
| Title |
|---|
| 梁安鹏等: "《药物集成 VI 化学原料药及药用辅料（一）》", 30 June 2008, article "磷霉素氨三丁醇", pages: 5655 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN108997424A (en) * | 2017-06-06 | 2018-12-14 | 湖南华纳大药厂手性药物有限公司 | A kind of simple and direct method for preparing fosfomycin trometamol |
| CN108997425A (en) * | 2017-06-06 | 2018-12-14 | 湖南华纳大药厂手性药物有限公司 | A method of preparing high-content fosfomycin trometamol |
| CN108997424B (en) * | 2017-06-06 | 2020-11-13 | 湖南华纳大药厂手性药物有限公司 | Simple method for preparing fosfomycin trometamol |
| CN108997425B (en) * | 2017-06-06 | 2020-11-13 | 湖南华纳大药厂手性药物有限公司 | Method for preparing high-content fosfomycin trometamol |
| WO2020147160A1 (en) * | 2019-01-18 | 2020-07-23 | 科大华采(武汉)生物科技股份有限公司 | Method for preparing fosfomycin trometamol |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101613361B (en) | Method for preparing cefoxitin sodium | |
| CN102134252B (en) | Preparation method of high-purity cefuroxime acid | |
| CN106566851B (en) | Preparation method of chloramphenicol compound | |
| CN101319246A (en) | Process for preparing cefixime | |
| CN102351902A (en) | Preparation method of fosfomycin monoamine butantriol | |
| CN103467495A (en) | Method for preparing cefixime compound | |
| CN102161667B (en) | Sulbenicillin sodium and sulbenicillin sodium used for injection | |
| CN104311597A (en) | Industrial production method of s-(-)-ornidazole disodium phosphate | |
| WO2017140072A1 (en) | Novel polymorphic cefuroxime sodium compound and preparation employing particle process crystal product molecular assembly and morphological optimization technique | |
| CN104193765B (en) | A kind of synthetic method of cefixime | |
| CN114685485B (en) | Synthesis method of pyridoimidazole thiopropionic acid anti-gout compound | |
| CN104447800A (en) | Synthesis technology of cefoxitin acid | |
| CN103897025A (en) | Preparation method of pidotimod | |
| CN103304582B (en) | Cefoxitin sodium compound, preparation method and pharmaceutical composition thereof | |
| CN109369611B (en) | Synthetic method of 4-chlorothiophene-2-carbonyl derivative | |
| CN101550146A (en) | Cefetamet pivoxil hydrochloride compound and preparation method thereof | |
| CN103044416A (en) | Synthetic method of Carumonam sodium | |
| CN107892676B (en) | The preparation method of Cefdinir active thioester | |
| CN102838620A (en) | Preparation process of amoxicillin sodium crystal | |
| CN110003238A (en) | A kind of preparation method of cefotiam | |
| CN104610280A (en) | Preparation method of cephalotin acid | |
| CN109912625B (en) | Process method for reducing ceftazidime impurity H | |
| CN104327098B (en) | A kind of cefetamet diisopropylamine | |
| WO2017140073A1 (en) | Cefathiamidine novel crystal compound using particle process crystal product molecular assembly and morphology optimisation technology and formulation thereof | |
| CN104910183B (en) | A kind of synthetic method of flucloxacillin sodium-hydrate |
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 |
Application publication date: 20120215 |