CN101928300B - New preparation method of pulveres fosfomycin tromethamine salt - Google Patents
New preparation method of pulveres fosfomycin tromethamine salt Download PDFInfo
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- CN101928300B CN101928300B CN200910272405XA CN200910272405A CN101928300B CN 101928300 B CN101928300 B CN 101928300B CN 200910272405X A CN200910272405X A CN 200910272405XA CN 200910272405 A CN200910272405 A CN 200910272405A CN 101928300 B CN101928300 B CN 101928300B
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Abstract
The invention relates to a new preparation method of pulveres fosfomycin tromethamine salt, which is simple and convenient and has low cost. The preparation method comprises the following steps: taking laevo-fosfomycin dextro-phenylethylamine salt as a raw material, and alkalifying the raw material with an alkali metal hydroxide for removing the dextro-phenylethylamine salt to obtain laevo-fosfomycin di-alkali metal salt aqueous solution; adding tromethamine acid inorganic salt aqueous solution to the obtained di-alkali metal salt aqueous solution, dehydrating at low temperature, and carrying out metathesis base exchange in methanol to filter out alkali metal inorganic salt; and adding an organic solvent to methanol solution to separate out the pulveres fosfomycin tromethamine salt, filtering and drying to obtain the pulveres fosfomycin tromethamine salt.
Description
Technical field
The present invention relates to a kind of synthetic new method of pulveres fosfomycin tromethamine salt.The present invention proposes easier a, method of synthetic pulveres fosfomycin tromethamine salt cheaply.
Background technology
Phosphonomycin is a Broad spectrum antibiotics.All responsive to staphylococcus, intestinal bacteria, meningococcus, gonococcus, Corynebacterium diphtheriae, Serratia, Bacillus proteus, Pseudomonas aeruginosa, dysentery bacterium and Hp etc., can suppress the synthetic of bacteria cell wall, be the sterilant of a kind of nursery stage, all inhibited to most of suis, Pseudomonas aeruginosa, Proteus mirabilis and part pneumobacillus and the negative mycetozoan of indoles.Phosphonomycin is applicable to urinary tract, respiratory tract, digestive tube, gynaecology, skin soft tissue and other site infections and septicemia.Oral administration can be treated intestinal tract infections, urinary tract infections, Serratia infection, Helicobacter pylori infection and blepharitis, hordeolum, otitis media, nasal sinusitis, dacryocystitis or the like; Intravenous injection can be treated gynaecopathias such as respiratory tract infection, urinary tract infection, septicemia and pelvic inflammatory disease, appendagitis, intra-uterine infection, and range of application is very extensive.
Pulveres fosfomycin tromethamine salt is clinical widely used oral phosphonomycin salt, and the main method of patent documentation report has following several:
(1) Spain's patent ES511527 is a raw material with phosphonomycin dextrorotation phenylethylamine salt, with the reaction of tromethamine salt sulfonate, adds the Virahol crystallization in methyl alcohol, and twice recrystallization obtains pulveres fosfomycin tromethamine salt again;
(2) European patent EP 1762573 is a raw material with phosphonomycin two basic metal, in methyl alcohol, react with monoamine trihydroxybutane dicarboxylate (as oxalic acid, tartrate, fumaric acid, toxilic acid etc.), remove dicarboxylic acid two an alkali metal salts of generation, concentrate, add 1: 1 ethanol/acetone mixed solvent crystallization, obtain pulveres fosfomycin tromethamine salt;
(3) Chinese patent CN1060470 is a raw material with phosphonomycin dextrorotation phenylethylamine salt, in low-temp methanol, generate the phosphonomycin free acid, with the Trometamol neutralization, concentrate again with the reaction of H type Zeo-karb, add C2-C5 alcohol or ketone crystallization, obtain pulveres fosfomycin tromethamine salt;
(4) Chinese patent CN1544440 is a raw material with phosphonomycin two an alkali metal salts, in low-temp methanol, generate the phosphonomycin free acid, with the Trometamol neutralization, concentrate again with the reaction of H type Zeo-karb, add C2-C5 alcohol or ketone crystallization, obtain pulveres fosfomycin tromethamine salt;
(5) Chinese patent CN1060657 is a raw material with the phosphonomycin calcium salt, with the reaction of monoamine trihydroxybutane list oxalate, removes by filter caoxalate in water, concentrates, and recrystallization obtains pulveres fosfomycin tromethamine salt;
(6) GB2062640 is a raw material with the two tromethamine salts of phosphonomycin, and with the tosic acid reacting by heating, crystallisation by cooling obtains pulveres fosfomycin tromethamine salt in ethanol;
(7) US5162309 is a raw material with the two tromethamine salts of phosphonomycin, with tosic acid and phosphonomycin dextrorotation phenylethylamine reactant salt, adds the ethanol crystallization in methyl alcohol, obtains pulveres fosfomycin tromethamine salt;
The manufacture method of above pulveres fosfomycin tromethamine salt can be divided into two classes: a class belongs to ion exchange method, the another kind of double decomposition that belongs to.Two class methods all have such or such deficiency, for example ion exchange method (CN1060470 and CN1544440) adopts H type Zeo-karb to make phosphonomycin salt become the phosphonomycin free acid, though there is not the problem of sulfonate wastewater treatment difficulty, but resin regeneration need consume many several times strong acid, and the phosphonomycin free acid is very unstable, and the easy open loop of epoxy bond generates glycol, influences quality product, moreover the methyl alcohol loss is big during concentrating under reduced pressure, also has methyl alcohol and alcoholic acid separation problem; Again for example in the double decomposition ES511527 and US5162309 have the risk of residual sulfonic acid and dextrorotation phenylethylamine in the product.In addition
Not only exist methyl alcohol and Virahol to be difficult to the problem of separating and recycling among the Spain patent ES511527, but also have the problem of sulfonate wastewater treatment difficulty;
European patent EP 1762573 exists also that methyl alcohol, acetone and ethanol are difficult to be separated and the problem of the recycling of carboxylate salt;
Chinese patent CN1060657 is to be raw material with the phosphonomycin calcium salt, the condition of crystallization and recrystallization is not described in this patent, and Fosmicin needs to react with calcium chloride from phosphonomycin dextrorotation phenylethylamine salt or phosphonomycin two an alkali metal salts and gets, total process is more complicated still, also will consider the recycling of caoxalate simultaneously.
U.S. Pat 5162309 and English Patent GB2062640 also exist methyl alcohol and alcoholic acid separation problem.
Summary of the invention
The objective of the invention is to solve the variety of issue that exists in the prior art, provide a kind of easier, practical, be the novel method of the synthetic pulveres fosfomycin tromethamine salt of raw material with phosphonomycin dextrorotation phenylethylamine salt cheaply.
Through lot of experiments, the inventor finds that under certain conditions, double decomposition (alkali exchange) reaction also can take place smoothly for Trometamol mineral acid acid salt and phosphonomycin two an alkali metal salts, generates pulveres fosfomycin tromethamine salt and inorganic salt.
Compared with the prior art, advantage of the present invention is: the one, and can residual sulfonic acid and dextrorotation phenylethylamine in the product; The 2nd, epoxy bond seldom open loop generates glycol, and quality product improves; The 3rd, solvent can reclaim easily, separate and utilize; The 4th, do not use sulfonic acid or organic acid, do not exist the sulfonic acid difficulty to recycle and problem of environment pollution caused, need not consider organic acid recycling problem yet; The 5th, mineral acid is inexpensive, and is even by product does not utilize, also very little to environmental influence; The 6th, the working condition requirement is gentle, and cost is low.
For the present invention, have some to further specify:
1, as the solvent of benzene extraction ethamine, its scope that can select is very wide, both can use single solvent, also can use mixed solvent, but the contriver thinks and compares with single solvent that mixed solvent does not have extra benefit, makes solvent recuperation utilize on the contrary again and will become complicated even difficult.Single solvent preferred cheap sherwood oil, hexanaphthene, toluene, methylene dichloride, trichloromethane, methyl tertiary butyl ether.
2, discover mixing salt in the preparation process, temperature and the water content in the mixing salt of controlling suitable thickening are very important.Temperature is low excessively to cause water ratio too high, may cause the dilution crystallization failure of back; The too high water ratio that causes of temperature is low excessively, also causes the metathesis (removing inorganic alkaline metal salt) in the methyl alcohol not thorough, influences quality product; By the control thickening temperature, can effectively control moisture content.
3, dilution crystalline solvent is selected also very crucial, though add many other solvents pulveres fosfomycin tromethamine salt crystallization from methanol solution is separated out, but the solvent that the inventor sees fit should satisfy several conditions: the one, do not form azeotrope with methyl alcohol, and be convenient to separating, utilizing again of methyl alcohol and diluting solvent in the crystalline mother solution.The 2nd, the intrinsic toxicity of solvent is little, should be two kind solvents.The 3rd, the boiling point of solvent should be not too high, so that the drying of product, otherwise the residual solvent in the product will become problem.The 4th, solvent should possess the ability of an amount of moisture content of dissolving, if the ability of dissolution with solvents moisture content is too low, layering or caking will occur in the dilution crystallisation process.Though the mixture of arbitrary proportion that can use any two or more solvents of mentioning among the present invention is compared with single solvent as dilution crystalline solvent, does not have extra benefit, make solvent recuperation utilize again will to become complexity even difficult on the contrary.
4, because hydrochloric acid and nitric acid are monoprotic acid, can not form acid salt truly.Therefore the inventor will be called " nominal acid salt hydrochlorate " or " nominal acid nitrate " according to 1: 2 mol ratio and the formulated solution of suitable quantity of water by Trometamol and hydrochloric acid or nitric acid.
Though 5 can use the mixture of the arbitrary proportion of any two or three Trometamol acid inorganic acid salt of mentioning among the present invention to prepare mixing salt, but compare with single inorganic salt, do not have extra benefit yet, make operating process become complicated even difficult on the contrary.
Implementation of the present invention is: phosphonomycin dextrorotation phenylethylamine salt is made pulveres fosfomycin tromethamine salt through two step chemical reactions, comprise the following steps:
1, a kind of is the method for the synthetic phosphonomycin monoamine butanetriol salt of raw material with phosphonomycin dextrorotation phenylethylamine salt, comprises the following steps:
(1) preparation phosphonomycin two aqueous solution of alkali metal salt
With phosphonomycin dextrorotation phenylethylamine salt and alkali metal hydroxide aqueous solution reaction, make left-handed phenylethylamine free, the left-handed phenylethylamine of organic solvent extraction obtains phosphonomycin two aqueous solution of alkali metal salt;
Temperature of reaction is controlled at below 30 ℃ in the above-mentioned steps (1); Alkali metal hydroxide is selected from wherein a kind of of sodium hydroxide, potassium hydroxide; Extract used organic solvent and select in the hydro carbons of boiling point below 150 ℃, halogenated hydrocarbon, the ethers any for use.These solvents comprise: pentamethylene, hexane, hexanaphthene, methylcyclohexane, ethylcyclohexane, heptane, heptane isomers, octane, octane isomer, sherwood oil, benzene,toluene,xylene, ethylbenzene, methylene dichloride, trichloromethane, tetrachloromethane, 1,1-ethylene dichloride, 1,1,1-trichloroethane, Ethylene Dichloride, trieline, zellon, ether, propyl ether, isopropyl ether, butyl ether, ethyl isobutyl ether, methyl tertiary butyl ether, Ethyl Tertisry Butyl Ether.
(2) preparation mixing salt
Add the Trometamol acid inorganic acid salt aqueous solution in phosphonomycin two aqueous solution of alkali metal salt, the vacuum concentration dehydration obtains mixing salt to doing then;
The acid inorganic acid salt is selected from wherein a kind of of hydrochloride, nitrate, vitriol, phosphoric acid salt respectively in the above-mentioned steps (2);
When inorganic acid salt was hydrochloride or nitrate, said acid inorganic acid salt was according to 1: 2 mol ratio and formulated nominal acid salt hydrochlorate or the acid nitrate of suitable quantity of water by Trometamol and hydrochloric acid or nitric acid; The thickening temperature is no more than 50 ℃.
(3) preparation pulveres fosfomycin tromethamine salt
Add methyl alcohol in mixing salt, the dissolving pulveres fosfomycin tromethamine salt removes by filter inorganic alkaline metal salt.Add the polar organic solvent dilution in the filtrate, pulveres fosfomycin tromethamine salt is separated out, filtration, drying obtain pulveres fosfomycin tromethamine salt.
In the above-mentioned steps (3) the used organic solvent of dilution be selected from boiling point 98-138 ℃, do not form wherein any of esters solvent azeotrope, that contain the alcohols of 4-5 carbon atom or contain 5-6 carbon atom with methyl alcohol.These solvents comprise: propyl carbinol, isopropylcarbinol, sec-butyl alcohol, the trimethyl carbinol, Pentyl alcohol, primary isoamyl alcohol, sec.-amyl alcohol, tertiary amyl alcohol, the 3-amylalcohol, 2-methyl-1-butene alcohol, 3-methyl-2-butanols, n-buty formate, tetryl formate, sec.-butyl formate, t-butyl formate, the formic acid n-pentyl ester, isoamyl formate, the secondary pentyl ester of formic acid, the formic acid tert-pentyl ester, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, tert.-butyl acetate, ethyl propionate, the propionic acid n-propyl, isopropyl propionate, positive butyl ester methyl esters, the butanic acid ethyl ester, methyl isobutyrate, ethyl isobutyrate, positive methyl valerate, methyl isovalerate, methyl trimethylacetate.
The present invention has following advantage: raw material is cheap and easy to get, toxicity is little; Reaction conditions gentleness, side reaction are few; Cost is low, be suitable for industrialization; Not only the three wastes of Chan Shenging are few, almost emit no waste water.
In order further to understand the present invention, further set forth the present invention with embodiment below.
Embodiment one: Trometamol bisul-phate method
Step (1), the preparation phosphonomycin disodium salt aqueous solution
Add 0.2mol 30% liquid caustic soda, 50ml water and 100ml toluene in the reaction flask, stir and cool to 5 ℃, add 0.1mol phosphonomycin dextrorotation phenylethylamine salt, treat all solids disappeared, stirred 30 minutes static layering below 15 ℃.The water intaking layer directly changes next step over to.
Step (2), preparation mixing salt
Add 0.1mol Trometamol bisul-phate (compound method: add 0.1mol Trometamol and 0.1mol sulfuric acid in the 50ml water) in phosphonomycin two aqueous solution of alkali metal salt, the cryoconcentration dehydration obtains mixing salt to doing then.Thickening temperature is no more than 50 ℃.
Step (3), preparation pulveres fosfomycin tromethamine salt
Add 250ml methyl alcohol in upwards going on foot the gained mixing salt, 30-40 ℃ was stirred 1 hour, and removed by filter sodium sulfate.Add the 250ml propyl carbinol in the filtrate, cooling is cooled to below 0 ℃, filters, and (1: 1V/V) washing, vacuum-drying below 50 ℃ 8 hours obtains the 18g pulveres fosfomycin tromethamine salt to filter cake, yield about 69% with 50ml propyl carbinol/methanol mixed solvent.
Embodiment two: Trometamol acid phosphate method
Step (1), the preparation phosphonomycin di-potassium aqueous solution
Add 0.2mol potassium hydroxide, 50ml water and 100ml methyl tertiary butyl ether in the reaction flask, stir and cool to 5 ℃, add 0.1mol phosphonomycin dextrorotation phenylethylamine salt, treat all solids disappeared, stirred 30 minutes static layering below 15 ℃.The water intaking layer directly changes next step over to.
Step (2), preparation mixing salt
Add the 0.1mol Trometamol acid phosphate aqueous solution (compound method: add 0.1mol Trometamol and 0.1mol phosphoric acid in the 50ml water) in the phosphonomycin di-potassium aqueous solution, the cryoconcentration dehydration obtains mixing salt to doing then.Thickening temperature is no more than 45 ℃.
Step (3), preparation pulveres fosfomycin tromethamine salt
Add 250ml methyl alcohol in upwards going on foot the gained mixing salt, 30-40 ℃ was stirred 1 hour, and removed by filter perlate salt.Add the 250ml n-buty formate in the filtrate, cooling is cooled to below 10 ℃, filters, filter cake 50ml n-buty formate/methanol mixed solvent (1: 1V/V) washing, vacuum-drying below 50 ℃ 8 hours obtains the 18.5g pulveres fosfomycin tromethamine salt, yield about 71%.
Embodiment three: Trometamol acid salt hydrochlorate method
Step (1), the preparation phosphonomycin disodium salt aqueous solution
Add 0.2mol 30% liquid caustic soda, 50ml water and 100ml methylene dichloride in the reaction flask, stir and cool to 5 ℃, add 0.1mol phosphonomycin dextrorotation phenylethylamine salt, treat all solids disappeared, stirred 30 minutes static layering below 15 ℃.The water intaking layer directly changes next step over to.
Step (2), preparation mixing salt
Add 0.1mol Trometamol acid salt acid salt aqueous solution (compound method: get 4.0mol/L hydrochloric acid 50ml, add the 0.1mol Trometamol, dissolving promptly) in the phosphonomycin disodium salt aqueous solution, the cryoconcentration dehydration obtains mixing salt to doing then.Thickening temperature is no more than 50 ℃.
Step (3), preparation pulveres fosfomycin tromethamine salt
Add 250ml methyl alcohol in upwards going on foot the gained mixing salt, 30-40 ℃ was stirred 1 hour, and removed by filter sodium-chlor.Add the 250ml primary isoamyl alcohol in the filtrate, cooling is cooled to below 10 ℃, filters, and (1: 1V/V) washing, vacuum-drying below 50 ℃ 8 hours obtains the 17.7g pulveres fosfomycin tromethamine salt to filter cake, yield about 68% with 50ml primary isoamyl alcohol/methanol mixed solvent.
Embodiment four: Trometamol acid nitrate process
Step (1), the preparation phosphonomycin disodium salt aqueous solution
Add 0.2mol 30% liquid caustic soda, 50ml water and 100ml hexanaphthene in the reaction flask, stir and cool to 5 ℃, add 0.1mol phosphonomycin dextrorotation phenylethylamine salt, treat all solids disappeared, stirred 30 minutes static layering below 15 ℃.The water intaking layer directly changes next step over to.
Step (2), preparation mixing salt
Add 0.1mol Trometamol acid nitrate aqueous solution (compound method: get 4.0mol/L nitric acid 50ml, add the 0.1mol Trometamol, dissolving promptly) in the phosphonomycin disodium salt aqueous solution, the cryoconcentration dehydration obtains mixing salt to doing then.Thickening temperature is no more than 50 ℃.
Step (3), preparation pulveres fosfomycin tromethamine salt crude product
Add 250ml methyl alcohol in upwards going on foot the gained mixing salt, 30-40 ℃ was stirred 1 hour, and removed by filter SODIUMNITRATE.Add the 250ml tertiary amyl alcohol in the filtrate, cooling is cooled to below 10 ℃, filters, and (1: 1V/V) washing, vacuum-drying below 50 ℃ 8 hours obtains the 18.2g pulveres fosfomycin tromethamine salt to filter cake, yield about 69.9% with 50ml tertiary amyl alcohol/methanol mixed solvent.
Claims (8)
1. the novel preparation method of a pulveres fosfomycin tromethamine salt comprises the following steps:
(1) preparation phosphonomycin two aqueous solution of alkali metal salt
With phosphonomycin dextrorotation phenylethylamine salt and alkali metal hydroxide aqueous solution reaction, make left-handed phenylethylamine free, the left-handed phenylethylamine of organic solvent extraction obtains phosphonomycin two aqueous solution of alkali metal salt;
(2) preparation mixing salt
Add the Trometamol acid inorganic acid salt aqueous solution in phosphonomycin two aqueous solution of alkali metal salt, the vacuum concentration dehydration obtains mixing salt to doing then;
(3) preparation pulveres fosfomycin tromethamine salt
Add methyl alcohol in mixing salt, the dissolving pulveres fosfomycin tromethamine salt removes by filter inorganic alkaline metal salt; Add the polar organic solvent dilution in the filtrate, pulveres fosfomycin tromethamine salt is separated out, filtration, drying obtain pulveres fosfomycin tromethamine salt; Wherein polar organic solvent is selected from propyl carbinol, isopropylcarbinol, sec-butyl alcohol, the trimethyl carbinol, Pentyl alcohol, primary isoamyl alcohol, sec.-amyl alcohol, tertiary amyl alcohol, 3-amylalcohol, 2-methyl-1-butene alcohol, 3-methyl-2-butanols; The ester class organic solvent of the said 5-6 of a containing carbon atom is selected from n-buty formate, tetryl formate, sec.-butyl formate, t-butyl formate, the formic acid n-pentyl ester, isoamyl formate, the secondary pentyl ester of formic acid, the formic acid tert-pentyl ester, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, tert.-butyl acetate, ethyl propionate, the propionic acid n-propyl, isopropyl propionate, methyl butyl, the butanic acid ethyl ester, methyl isobutyrate, ethyl isobutyrate, positive methyl valerate, methyl isovalerate, methyl trimethylacetate.
2. according to the method for claim 1, it is characterized in that said alkali metal hydroxide in the step (1) is selected from wherein a kind of of sodium hydroxide, potassium hydroxide.
3. according to the method for claim 1, it is characterized in that temperature of reaction is controlled at below 30 ℃ in the step (1).
4. according to the method for claim 1, it is characterized in that the used organic solvent of extraction in the step (1) selects any in the hydro carbons of boiling point below 150 ℃, halogenated hydrocarbon, the ethers for use.
5. according to the method for claim 1, it is characterized in that said acid inorganic acid salt in the step (2) is selected from wherein a kind of of hydrochloride, nitrate, vitriol, phosphoric acid salt.
6. according to the method for claim 1, it is characterized in that the thickening temperature is no more than 50 ℃ in the step (2).
7. according to the method for claim 1, it is characterized in that when said inorganic acid salt is hydrochloride or nitrate in the step (2) said acid inorganic acid salt is according to 1: 2 mol ratio and formulated nominal acid salt hydrochlorate or the acid nitrate of suitable quantity of water by Trometamol and hydrochloric acid or nitric acid.
8. according to the method for claim 4, it is characterized in that said varsol is pentamethylene, hexane, hexanaphthene, methylcyclohexane, ethylcyclohexane, heptane, heptane isomers, octane, octane isomer, sherwood oil, benzene,toluene,xylene, ethylbenzene; Said halogenated hydrocarbon solvent is methylene dichloride, trichloromethane, tetrachloromethane, 1,1-ethylene dichloride, 1, Ethylene Dichloride, trieline, zellon; Said ethers is ether, propyl ether, isopropyl ether, butyl ether, ethyl isobutyl ether, methyl tertiary butyl ether, Ethyl Tertisry Butyl Ether.
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| 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 |
| CN109608497B (en) * | 2019-01-18 | 2020-07-31 | 科大华采(武汉)生物科技股份有限公司 | Preparation method of fosfomycin trometamol |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1060657A (en) * | 1990-10-19 | 1992-04-29 | 山东省医药工业研究所 | Making method of phosphorus mycomycin slow blood acid amine salt |
| CN1544440A (en) * | 2003-11-27 | 2004-11-10 | 东北制药总厂 | Novel pulveres fosfomycin trometamol synthetic method |
| EP1762573A1 (en) * | 2005-09-08 | 2007-03-14 | Interquim, S.A. De C.V. | A process for the preparation of fosfomycin salts |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1060657A (en) * | 1990-10-19 | 1992-04-29 | 山东省医药工业研究所 | Making method of phosphorus mycomycin slow blood acid amine salt |
| CN1544440A (en) * | 2003-11-27 | 2004-11-10 | 东北制药总厂 | Novel pulveres fosfomycin trometamol synthetic method |
| EP1762573A1 (en) * | 2005-09-08 | 2007-03-14 | Interquim, S.A. De C.V. | A process for the preparation of fosfomycin salts |
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