CN100560588C - Preparation of cefepime hydrochlorice by sodium salt precipitation method - Google Patents
Preparation of cefepime hydrochlorice by sodium salt precipitation method Download PDFInfo
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- CN100560588C CN100560588C CNB2007101031469A CN200710103146A CN100560588C CN 100560588 C CN100560588 C CN 100560588C CN B2007101031469 A CNB2007101031469 A CN B2007101031469A CN 200710103146 A CN200710103146 A CN 200710103146A CN 100560588 C CN100560588 C CN 100560588C
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Abstract
The present invention relates to a kind of method for preparing the cefepime hydrochloride.This method is adjusted to slightly acidic to sulfuric acid cefepime solution to neutral with water miscible alkaline sodium salt (sodium-acetate, Sodium.alpha.-hydroxypropionate, Sodium isooctanoate, yellow soda ash, sodium bicarbonate, sodium hydroxide or its any mixture), adds sodium sulfate, sodium pyrosulfate or its hydrate that organic solvent deposit goes out to generate.Add the hydrochloric acid salify then and obtain the cefepime hydrochloride.This method has effectively been avoided the degraded of cefepime, has improved the yield and the purity of product; Greatly reduce of the corrosion of acid feed liquid to equipment; Obviously reduce the consumption of organic solvent, improved production efficiency.
Description
Technical field
The present invention relates to a kind of preparation method of cephalosporin compound, especially is the method for feedstock production cefepime hydrochloride with the sulfuric acid cefepime.
Background technology
Cefepime (cefepime, likes I) be the 4th generation cephalosporin injection microbiotic, Gram-negative bacteria, gram-positive microorganism and anerobe all had good antibacterial activity, simultaneously β-Nei Xiananmei is shown advantages of higher stability, have antimicrobial spectrum and anti-microbial activity more widely than third generation cephalosporin antibiotic.Be used for the treatment of severe infections clinically.Cefepime document the earliest is a U.S. Pat 4,406,899.
Cefepime is a kind of thermally labile and water-soluble very big neutral inner salt, and its structure is as shown below.Because there is the carboxyl negative ion in purified cefepime, easily combines with proton in the aqueous solution, impels the ionization equilibrium of water to produce more hydroxide ion, makes solution be weakly alkaline.Reactions such as degraded and open loop take place in cefepime easily under the weak base condition, cause content to descend, and impurity increases.And the solid cefepime is metamict, be difficult to dewater fully, so the chemical stability of cefepime is relatively poor, is difficult to standing storage.
U.S. Pat 4,994,451 and US 5,244,891 disclose and cefepime is made forms such as corresponding hydrochloride, vitriol or nitrate can improve its purity and stability.The cefepime Hydrochloride of crystalline state has two kinds of forms, and a kind of is monohydrate (US 5,244,891), and another kind is dihydrate (US 5,391,729).The cefepime of pharmaceutical industries production at present and use is the cefepime Hydrochloride monohydrate.The structure of one hydration cefepime Hydrochloride is shown in (II) formula:
Cefepime Hydrochloride acidity is stronger, and injection hydrochloric acid cephalo can cause pain in human body.In actual applications, cefepime Hydrochloride often mixes by a certain percentage with alkaline powder (for example arginine), makes the mixed powder of pH value of aqueous solution between 3.5～7.0, adds water, physiological saline or glucose solution dissolving before the use again.
U.S. Pat 4,994 points out among 451 (1991-2-19) that the solubleness of sulfuric acid cefepime in water is little, from the aqueous solution, separates easily, and the product purity height.This information indicating by forming the sulfuric acid cefepime, remove impurity, change into hydrochloride then, be that the highly purified cefepime Hydrochloride of preparation is a kind of effective means.
U.S. Pat 4,910,301, US 4,994,451, US 5,244,891 disclose the method for preparing cefepime Hydrochloride, adopt the sulfuric acid molecule in ion exchange resin or the weakly base resin absorption sulfuric acid cefepime, make the free cefepime, in free cefepime solution, add hydrochloric acid then, preparation cefepime hydrochloride.At US 5,244, among 891 the ExampleXI, use liquid resin Amberlite LA-2 to absorb sulfuric acid molecule, but need simultaneously to use the harmful freonll-11 of environment; In Example XII, introduced the method for in water, utilizing excessive solid weakly base resin to absorb sulfuric acid molecule, but yield data is not provided.Discover, use solid resin can absorb a large amount of cefepime feed liquids, be not easy washing and recycling, cause yield on the low side.And the recovery of solid resin is again with influencing quality product easily, because the cephalo feed liquid of resin inside is difficult to thorough removing, and the cefepime feed liquid decompose easily at normal temperatures (1, Antimicrobial Agents andChemotherapy, June 2003, p.1991-1994.2、Journal?of?Antimicrobial?Chemotherapy(2003)，651-658。3、Antimicrobial?Agents?and?Chemotherapy，Aug.2002，p.2327-2332。), degradation production can enter feed liquid when used next time, for product brings unnecessary impurity.
There is European patent EP 1762570A1 to disclose a kind of method of removing sulfuric acid molecule with sodium hydroxide recently.This method transfers to weakly alkaline to sulfuric acid cefepime solution with sodium hydroxide, generates sodium sulfate and free cefepime, adds a large amount of acetone precipitation sodium sulfate again.In actual production, this method makes the cefepime long period be exposed in the weakly alkaline environment, causes feed liquid color burn and impurity to increase easily, finally influences the purity of product.
Summary of the invention
The present invention is unexpected to find that the solubleness of sodium sulfate and sodium pyrosulfate and hydrate thereof is all very little in water-containing organic solvent (for example methyl alcohol, ethanol, Virahol, acetone, tetrahydrofuran (THF), acetonitrile), thereby provides a kind of more effective commentaries on classics salt method that the sulfuric acid cefepime is converted into the cefepime hydrochloride.One of feature of the present invention is to precipitate sodium salt under solutions of weak acidity, has effectively avoided the problem of following decomposition of cefepime alkaline condition and color burn, has improved quality product.In addition, the crystallization feed liquid is little to the corrodibility of equipment, and the organic solvent amount of use obviously reduces, and has saved production cost, and has enhanced productivity greatly.
The method that the present invention prepares cefepime hydrogen salt hydrochlorate is:
1) in the aqueous solvent system,, regulates pH below 6.5 with sulfuric acid cefepime and the reaction of water miscible alkaline sodium salt.
2) add water-miscible organic solvent and separate out sodium sulfate, sodium pyrosulfate, sodium sulfate hydrate or sodium pyrosulfate hydrate.
3) will operate 2) in the sodium salt solid that produces remove by solid-liquid separation.
4) will operate 3) in the cefepime filtrate that obtains regulate pH 1.0～1.5 with hydrochloric acid, add water-miscible organic solvent and separate out cephalo pyrrole crystal of hydrochloride.
Operate 1 among the present invention) described " aqueous solvent system " be meant that (1) have only a kind of solvent of water or (2) aqueous organic solvent that can be miscible with water, described organic solvent comprises: the mixed solvent of methyl alcohol, ethanol, Virahol, acetone, tetrahydrofuran (THF), acetonitrile or above-mentioned any solvent.Described " mixed solvent of above-mentioned any solvent " is meant the mixed solvent of above-mentioned two or more solvent, as: methyl alcohol+acetone, ethanol+methyl alcohol, ethanol+acetone+tetrahydrofuran (THF) etc.
The water miscible alkaline sodium salt of indication of the present invention can be the arbitrary composition of sodium-acetate (sodium acetate), Sodium.alpha.-hydroxypropionate, Sodium isooctanoate (2 ethyl hexanoic acid sodium), yellow soda ash, sodium bicarbonate, sodium hydroxide and above-mentioned substance, as: sodium-acetate+Sodium.alpha.-hydroxypropionate, Sodium isooctanoate+yellow soda ash, yellow soda ash+sodium-acetate+sodium hydroxide etc.For example, 2 moles sodium-acetate and the reaction of 1 mol sulfuric acid cefepime generate 1 mole of cefepime, 1 mol sulfuric acid sodium hydrate and 2 molar acetates.The neutralized weakly alkaline of cefepime of the slightly acidic of acetic acid, Bao Hu cefepime is not decomposed effectively.Yellow soda ash or sodium bicarbonate and the reaction of sulfuric acid cefepime, the carbonic acid gas of generation also can play same regulating effect.From economic angle, inorganic salt more have cost advantage than organic acid salt.Experiment is also found, regulate pH to 5.5～6.5 even use sodium hydroxide merely, also can effectively remove sulfuric acid molecule (can judge), but the stability of cefepime is much higher during than pH 7.7 (EP 1762570A1 embodiment 1) from the ignition residue value of product.Above-mentioned reaction all can be carried out at normal temperatures, does not need cold condition, has simplified operation.
Aforesaid operations 1) in, pH value of solution is between 5.5～6.5, and cefepime departs from weakly alkaline iso-electric point, and solubleness increases.Therefore dissolving the required good solvent of cefepime can reduce, and can obviously reduce final crystallization and separate out the required poor solvent of cefepime Hydrochloride (for example acetone) consumption.Both save production cost, improved throughput again.
Can be in the aforesaid method in operation 1) later stage of reaction adds activated carbon decolorizing, and sedimentary sodium salt and breeze filter in the lump.In case of necessity also can be in operation 3) add activated carbon decolorizing and absorption pyrogen in the filtrate of gained.
Aforesaid operations 2) in, described " water-miscible organic solvent " can be the mixture of methyl alcohol, ethanol, Virahol, acetone, tetrahydrofuran (THF), acetonitrile or their arbitrary proportions, as: methyl alcohol+acetone, ethanol+methyl alcohol, ethanol+acetone+tetrahydrofuran (THF) etc.Preferred acetone.
Aforesaid operations 3) in, the method for described " solid-liquid separation " refers to filter or method well known to those skilled in the art such as centrifugal.Can also comprise in case of necessity filter cake is washed.
Aforesaid operations 3) resulting filtrate is acetate, lactic acid salt, 2-ethylhexoate, supercarbonate or the free cefepime solution of cefepime.If add strong acid such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid again, can generate corresponding hydrochloride, nitrate, phosphoric acid salt, vitriol respectively.The solubleness of these salt is lower, can separate out by the method crystallization of the miscible organic solvent of cooling or adding and water.U.S. Pat 5,244,891 have put down in writing relevant salifying method.
Aforesaid operations 4) in, described " water-miscible organic solvent " can be the mixture of ethanol, Virahol, acetone, tetrahydrofuran (THF), acetonitrile or their arbitrary proportions.Preferred acetone.
It is a kind of than US 5,244 that the present invention also provides, and 891 and the cefepime crystal of hydrochloride condition that more has superiority of EP 1762570A1, it is littler to the corrodibility of equipment to have feed liquid, the characteristics that the organic solvent amount of use obviously reduces.Find in the test, in the cefepime hydrochloride crystal of in the water of pH 1.6～1.8 and acetone system, separating out, the mol ratio of HCl and cefepime is less than 2, dissolving back pH value is higher, and the residual quantity of acetone is often greater than 1% (pharmacopeia Chinese, the U.S. all require the acetone of commodity cefepime hydrochloride residual less than 0.5%).In the cefepime hydrochloride crystal that pH separates out in greater than 1.8 water and acetone system, the residual quantity of acetone is bigger, and can't remove by the drying means that is warming up to 50 ℃.We suspect that small amount of acetone has entered lattice, and have replaced the position of former HCl.When adding the excessive HCl of trace in the solution and reaching pH 1.5 when following, the residual phenomenon of acetone does not just have appearance again.When pH is between 1.0～1.5, use more a spot of organic solvent (as 9～10 times of volume ratios to the acetone of water consumption) just can access yield, and crystallization effect repeatability is good up to 91% qualified product.Test is found, further increase the acetone consumption and not only do not increase yield, and product colour is deepened impurity increase, purity decline.Crystallization does not only have yield and qualitative improvement under the bigger condition of acidity, and has increased the chance of equipment corrosion, and the pressure of liquid waste disposal.
The equipment corrosion that acidic conditions causes can bring serious quality problems with medicine to aseptic injection.When feed acidity was big, successive production can make stainless steel equipment surfaces such as pipeline, strainer, crystallization kettle cause corrosion spalling, may cause the key indexs such as heavy metal, clarity, clarity of injection medicine to worsen.Method of the present invention and patent US 5,244,891 compare with the EP1762570A1 disclosed method, and the hydrochloric acid consumption reduces, and feed liquid is littler to the corrodibility of equipment, and crystallization effect repeatability is good.
The method that the present invention prepares the cefepime hydrochloride has reduced cefepime decomposes under weak basic condition, has improved the productive rate of cefepime hydrochloride; Reduced the consumption of organic solvent, reduced pollution when having reduced production cost environment; Also reduced of the corrosion of acid feed liquid simultaneously, prolonged the work-ing life of production unit, saved production cost, also improved the quality of product equipment.Therefore have the favorable industrial using value, guaranteed long-term continual and steady high-quality production.
Specific embodiment
Further specify the present invention with the embodiment for preparing two hydrochloric acid cefepime monohydrates below, and unrestricted the present invention.
Embodiment 1
(15～25 ℃) are dissolved in 171g Sodium isooctanoate (1.03mol) in 900mL water and the 200mL acetone under the normal temperature, effectively stir down to add 300g sulfuric acid cefepime (0.52mol, weight is by anhydride) in batches, form the pulpous state system of good fluidity.Add 1600mL acetone and proper amount of active carbon after 10 minutes, stirred 30 minutes.Centrifugal or suction filtration is isolated solid.With 2: 1 (v/v) mixing solutionss of acetone-water 500mL washing leaching cake, merging filtrate.Stir down and in filtrate, add 18%HCl to pH 1.0～1.5.Add 8L acetone then in 1 hour.System is cooled to 5～10 ℃ again, continues to stir 1 hour.Suction filtration.The filter cake washing with acetone, 40 ℃ of following vacuum-dryings must about 270g white crystalline powder.Purity 99.7%, water content are 3.8% (K-F method), acetone residual 0.25%.Product is a cefepime dichloride hydrogen salt monohydrate.All quality index meet the American Pharmacopeia requirement.
Embodiment 2
(15～25 ℃) are added to 300g sulfuric acid cefepime (0.52mol, weight is by anhydride) in the 900mL water under the normal temperature, and the aqueous sodium hydroxide solution of dropping about 20% is between the system pH 5.5～6.5 under the vigorous stirring.Add 2100mL acetone and proper amount of active carbon then, stirred 30 minutes.Centrifugal or suction filtration is isolated solid.With 2: 1 (v/v) mixing solutionss of acetone-water 500mL washing leaching cake, merging filtrate.Stir down and in filtrate, add 30%HCl to pH 1.0～1.5.Add 8L acetone then in 1 hour.System is cooled to 5～10 ℃ again, continues to stir 1 hour.Suction filtration.The filter cake washing with acetone, 40 ℃ of following vacuum-dryings must about 270g white crystalline powder.Purity is more than 99.7%, and water content is 3～4%, and acetone is residual less than 0.4%.Product is cefepime dichloride hydrogen salt monohydrate equally.All quality index meet the American Pharmacopeia requirement.
Claims (10)
1, a kind of method for preparing the cefepime hydrochloride is characterized in that may further comprise the steps:
1) in the aqueous solution, 1 mol sulfuric acid cefepime and the weakly alkaline sodium salt reaction that contains 2 moles of sodium ions;
2) add water-miscible organic solvent, be settled out sodium sulfate, sodium pyrosulfate, sodium sulfate hydrate or sodium pyrosulfate hydrate;
3) solid-liquid separation is removed above-mentioned sodium salt precipitation;
4) filtrate is regulated pH 1.0～1.5 with hydrochloric acid, adds water-miscible organic solvent, separates out cefepime hydrochloride crystal.
2, method according to claim 1 is characterized in that: described weakly alkaline sodium salt is any mixture of sodium-acetate, Sodium.alpha.-hydroxypropionate, Sodium isooctanoate, sodium bicarbonate, yellow soda ash or above-mentioned weakly alkaline sodium salt.
3, method according to claim 1 is characterized in that: described weakly alkaline sodium salt is Sodium isooctanoate or sodium bicarbonate.
4, method according to claim 1 is characterized in that: step 2) described organic solvent comprises the mixed solvent of methyl alcohol, ethanol, Virahol, acetone, tetrahydrofuran (THF), acetonitrile or above-mentioned any solvent.The described organic solvent of step 4) comprises the mixed solvent of ethanol, Virahol, acetone, tetrahydrofuran (THF), acetonitrile or above-mentioned any solvent.
5, method according to claim 1 is characterized in that: described step 2) and the organic solvent of step 4) be acetone.
6, a kind of method for preparing the cefepime hydrochloride is characterized in that may further comprise the steps:
1) in the aqueous solution of sulfuric acid cefepime, regulates pH 5.5～6.5 with aqueous sodium hydroxide solution;
2) adding water-miscible organic solvent, be settled out sodium sulfate, sodium pyrosulfate, sodium sulfate hydrate or sodium pyrosulfate hydrate;
3) solid-liquid separation is removed above-mentioned sodium salt precipitation;
4) regulate pH 1.0～1.5 with hydrochloric acid in the filtrate, add water-miscible organic solvent, separate out cefepime hydrochloride crystal.
7, method according to claim 6 is characterized in that: step 2) described organic solvent comprises the mixed solvent of methyl alcohol, ethanol, Virahol, acetone, tetrahydrofuran (THF), acetonitrile or above-mentioned any solvent; The described organic solvent of step 4) comprises the mixed solvent of ethanol, Virahol, acetone, tetrahydrofuran (THF), acetonitrile or above-mentioned any solvent.
8, method according to claim 6 is characterized in that: step 2) and the described organic solvent of step 4) be acetone.
9, according to claim 1 or 6 described methods, the crystallization method that it is characterized in that the cefepime Hydrochloride hydrate is to separate out the cefepime Hydrochloride hydrate in the aqueous solution of pH1.0～1.5.
10, method according to claim 9 is characterized in that: contain any mixture that total amount at least is equivalent to acetic acid, lactic acid, isocaprylic acid or these three kinds of acid of cefepime molar weight in the solution simultaneously.
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| CN102010433B (en) * | 2010-12-02 | 2011-11-16 | 郝志艳 | Cefepime hydrochloride compound and new preparation method thereof |
| CN108083298B (en) * | 2018-01-15 | 2020-03-31 | 东南大学 | Method for preparing potassium sulfate nanocrystalline |
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Address after: Shenzhen City, Guangdong Province, 518040 Shennan Road No. 6009 Che Kung Temple Green Plaza building 37 layer Patentee after: Shenzhen Salubris Pharmaceuticals Co., Ltd. Address before: 518040, 1901, 1902, 1903, 1923, Shennan Exhibition Center, 6007 Shennan Road, Shenzhen, Guangdong, Futian District Patentee before: Shenzhen Salubris Pharmaceuticals Co., Ltd. |
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Granted publication date: 20091118 Termination date: 20200427 |