CN102250120A - Method for preparing nafcillin sodium monohydrate - Google Patents
Method for preparing nafcillin sodium monohydrate Download PDFInfo
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- CN102250120A CN102250120A CN2011101387520A CN201110138752A CN102250120A CN 102250120 A CN102250120 A CN 102250120A CN 2011101387520 A CN2011101387520 A CN 2011101387520A CN 201110138752 A CN201110138752 A CN 201110138752A CN 102250120 A CN102250120 A CN 102250120A
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- nafcillin sodium
- nafcillin
- anhydride
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- organic solvent
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Abstract
The invention discloses a method for preparing nafcillin sodium monohydrate. The method comprises the following steps of: performing freeze drying on an aqueous solution of nafcillin sodium serving as an initial raw material to obtain nafcillin sodium anhydride; and dissolving the nafcillin sodium anhydride in a 1.0 to 3.0 weight percent organic solvent, and performing hydration reaction to add crystal water to obtain the nafcillin sodium monohydrate. The nafcillin sodium monohydrate prepared by the method has high purity, the content of over 99.5 percent, high yield and low cost; moreover, the organic solvent is small in using amount and easily recovered, the pollution to the environment is furthest reduced, and the method is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of semisynthetic antibiotics Nafcillin sodium, particularly relate to a kind of method for preparing nafcillin sodium-hydrate by the nafcillin sodium water solution.
Background technology
Nafcillin sodium has another name called WY-3277, NAF, chemical name (2S, 5R)-3,3-dimethyl-6-(2-oxyethyl group-1-naphthyl)-7-oxidation-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid sodium salt monohydrate, molecular formula C
21H
21O
5N
2SNaH
2O, molecular weight 454.49, trade(brand)name Unipen is is at first researched and developed by U.S. Wyeth company, be applicable to the infectation of bacteria of the drug-fast staphylococcal infections of penicillin and other penicillin sensitivity, as: septicemia, endocarditis, pyothorax, liver abscess, pneumonia, osteomyelitis etc.
The bibliographical information of relevant Nafcillin sodium synthetic method was many in recent years, but really the synthetic method of suitable suitability for industrialized production is also few.E.G.BRAIN (J.Chem.Soc.1963:491) report obtains xanchromatic Nafcillin sodium anhydride to the nafcillin sodium water solution of preparation by evaporated under reduced pressure, the Nafcillin sodium crude product that this processing method obtains is clamminess, poor crystal form, color and luster is greater than yellow or yellowish green No. 5, content lower (high-efficient liquid phase analysis content is about 80%), the Nafcillin sodium crude product of preparation must just can obtain the Nafcillin sodium finished product through refinement treatment, its reason be because of solution medium be water, distillation temperature is higher, and the part Nafcillin sodium destruction that is decomposed is arranged in still-process.
CN 101659670A report is the synthetic Nafcillin sodium of starting raw material with nafcillin acid, and this method shortcoming is acetone the consumption too big 40-50 of nafcillin acid charging capacity (is doubly), and production capacity is little, and the manufacturing cost height is not suitable for suitability for industrialized production.
CN 101781315A report is a starting raw material with 2-hydroxyl-1-naphthoic acid, through ethylization, hydrolysis, chlorination, coupling, the synthetic target product of salify five steps reaction, the similar patent CN 101659670A of the salifiable method of final step reported method in the method, there is above-mentioned shortcoming equally, is not suitable for suitability for industrialized production.
CN 101456869A report is a starting raw material with 2-oxyethyl group-1-naphthoic acid, makes the Nafcillin sodium crude product through chloride, condensation, acidifying, alkalization four-step reaction.The shortcoming of this method is that prepared Nafcillin sodium is that form with the aqueous solution exists, because penicillin medicine is unstable in the aqueous solution, storage period long or temperature high beta-lactam nucleus very easily hydrolysis destroy and lose anti-microbial activity, can produce a series of degraded products simultaneously, influence drug safety.In addition, exist with aqueous solution form and also be unfavorable for storing transportation.
Summary of the invention
The objective of the invention is to overcome above deficiency, provide that a kind of production capacity is big, cost is low, Functionality, quality and appealing design, good stability, be convenient to store transportation, processing method environmental protection, be fit to the preparation method of the nafcillin sodium-hydrate of suitability for industrialized production.
The present invention is that the nafcillin sodium water solution for preparing with CN 101456869 methods is a starting raw material, prepare the Nafcillin sodium anhydride through lyophilize, again Nafcillin sodium anhydride crystal water on hydration reaction is made target compound, the concrete preparation method of its nafcillin sodium-hydrate may further comprise the steps:
1), be starting raw material with the nafcillin sodium water solution of 20-30wt%, obtained by freeze drying Nafcillin sodium anhydride;
2), Nafcillin sodium anhydride that step 1) is made is dissolved in the organic solvent acetone or butanone that water content is 1.0-3.0wt%, aseptic condition stirs down and is warmed up to 40-50 ℃, adds an amount of crystal seed, insulation reaction 2-3 hour;
3), cooling 1-2 hour, filter, take off mother liquor, after filter cake making beating washing is drained, pulverize, vacuum-drying gets nafcillin sodium-hydrate.
Wherein, step 2) in the consumption of organic solvent be Nafcillin sodium anhydride weight 4-12 doubly, preferred 8 times; The temperature of organic solvent dissolving Nafcillin sodium anhydride is controlled at 20-33 ℃, and preferred range is 28-30 ℃.
Further, the preferred 44-48 of insulation reaction temperature step 2) ℃.
Among the above-mentioned preparation method, described nafcillin sodium water solution before lyophilize, add earlier gac decolour handle after, will filter through the decarbonization filtering device again and obtain filtrate and carry out lyophilize.
Among the above-mentioned preparation method of the present invention, the Nafcillin sodium anhydride moisture content that obtains through lyophilize is below 2.5%, and the nafcillin sodium content is (analysis of HPLC method) more than 90%.
Compared with prior art, the present invention has mainly carried out following improvement.
1, behind the synthetic nafcillin sodium water solution, do not propose acid and directly obtain the Nafcillin sodium anhydride by freezing the cool-drying method, its advantage is: 1) quality aspect, because of the penicillins product under hot conditions dry beta-lactam nucleus very easily open loop destroy to produce by product, very big to quality influence, take cold drying, guaranteed the quality of product to greatest extent; 2) cost aspect directly obtains the sodium salt anhydride by cryochem from the nafcillin sodium water solution, not only got rid of and analysed acid used extraction agent and souring agent, but also shortened preparation section, and manufacturing cost descends significantly; 3) environmental protection aspect, cryodesiccated solution are water mutually, can not pollute environment in drying process, are optimal environmental type preparation methods, and simple to operate, are more suitable for suitability for industrialized production.
2, to compare advantage bigger for the method for crystal water and bibliographical information method on the Nafcillin sodium anhydride, be mainly reflected in following several respects: 1) in the present invention the used consumption of organic solvent of crystal water be Nafcillin sodium anhydride charging capacity 4-12 doubly about, not only reduced the solvent consumption greatly, compare with the patent report method, use the equipment capacity of equal conditions to increase significantly, extraction agent acetone consumption is no less than 40 times of nafcillin acid input amount among the CN 101659670A, the solvent consumption is big, consumption is many, production capacity is little, the cost height, and also strengthened the cost expenditure for the solvent recovery in later stage, and be only limited to small test, be not suitable for suitability for industrialized production, CN 101781315A method and CN 101659670A roughly the same do not have implementary value equally aspect suitability for industrialized production; 2) the present invention selects the organic solvent of water content 1～3% for use, its advantage is to need not special rectifying device when reclaiming organic solvent, having saved increases the extensive fund input of rectifying tower equipment (because of solvent for use of the present invention is the low carbon chain ketone, its polarity is stronger, dissolve each other with water, can producing azeotropic in common still-process, to cause reclaiming solvent moisture bigger than normal, water content is all about 2%, investigate checking by technology, apply mechanically and reclaim solvent under the situation that does not influence salify productive rate quality, can also satisfy the later stage and go up crystal water reaction institute water requirement, cut off the technology that added the water simplified control).
The nafcillin sodium-hydrate purity height that the present invention prepares, content reaches more than 99.5%, the productive rate height, cost is low, and the organic solvent consumption is little, easily reclaims, and has reduced the pollution to environment to greatest extent, is fit to suitability for industrialized production.
Embodiment
Embodiment 1.
The 3kg gac is joined in the nafcillin sodium water solution of 300L concentration about 24%, stir the half an hour of decolouring, through taking off the charcoal press filtration, the filtrate special-purpose stainless dish of freeze-drying of packing into, go into the Freeze Drying Equipment lyophilize and get Nafcillin sodium anhydride 71kg, content 93.2%, color and luster is less than No. 3, yellow-green colour.
Above-mentioned Nafcillin sodium anhydride 71kg is joined in the acetone soln of 560kg water content 2.5%, temperature raising to 28 ℃ stirring and dissolving, 10 minutes molten clear, add the 1kg gac and stir decolouring 20 minutes, be pressed in the sterilisable chamber crystallizer through carbon removal, degerming, defeathering coordinate filter then, open to stir and be warming up to 2 hours precipitation and crystallizations of 44 ℃ of insulated and stirred, the logical tap water cooling of crystallizer interlayer is 1 hour then, fundatrix liquid is taken off in filtration, filter cake is cold-draw half an hour again, pulverize sabot and go into baking oven, vacuum-drying gets nafcillin sodium-hydrate aseptic powder 65.1kg, content 99.7%.
Embodiment 2.
The 3kg gac is joined in the nafcillin sodium water solution of 250L concentration about 28%, stir the half an hour of decolouring, through taking off the charcoal press filtration, the filtrate special-purpose stainless dish of freeze-drying of packing into, go into the Freeze Drying Equipment lyophilize and get Nafcillin sodium anhydride 72kg, content 92.8%, color and luster is less than No. 3, yellow-green colour.
Above-mentioned Nafcillin sodium anhydride 72kg is joined in the butanone solution of 570kg water content 2.0%, temperature raising to 30 ℃ stirring and dissolving, 15 minutes molten clear, add the 1kg gac and stir decolouring 20 minutes, be pressed in the sterilisable chamber crystallizer through carbon removal, degerming, defeathering coordinate filter then, open to stir and be warming up to 3 hours precipitation and crystallizations of 48 ℃ of insulated and stirred, the logical tap water cooling of crystallizer interlayer is 1.5 hours then, fundatrix liquid is taken off in filtration, filter cake is cold-draw half an hour again, pulverize sabot and go into baking oven, vacuum-drying gets nafcillin sodium-hydrate aseptic powder 65.9kg, content 99.8%.
Embodiment 3.
The 3kg gac is joined in the nafcillin sodium water solution of 350L concentration about 20%, stir the half an hour of decolouring, through taking off the charcoal press filtration, the filtrate special-purpose stainless dish of freeze-drying of packing into, go into the Freeze Drying Equipment lyophilize and get Nafcillin sodium anhydride 71.8kg, content 93.0%, color and luster is less than No. 3, yellow-green colour.
Above-mentioned Nafcillin sodium anhydride 71.8kg is joined in the acetone soln of 400kg water content 1.5%, temperature raising to 33 ℃ stirring and dissolving, 12 minutes molten clear, add the 1kg gac and stir decolouring 20 minutes, be pressed in the sterilisable chamber crystallizer through carbon removal, degerming, defeathering coordinate filter then, open to stir and be warming up to 2.5 hours precipitation and crystallizations of 45 ℃ of insulated and stirred, the logical tap water cooling of crystallizer interlayer is 1 hour then, fundatrix liquid is taken off in filtration, filter cake is cold-draw half an hour again, pulverize sabot and go into baking oven, vacuum-drying gets nafcillin sodium-hydrate aseptic powder 65.5kg, content 99.7%.
Embodiment 4.
The 3kg gac is joined in the nafcillin sodium water solution of 240L concentration about 30%, stir the half an hour of decolouring, through taking off the charcoal press filtration, the filtrate special-purpose stainless dish of freeze-drying of packing into, go into the Freeze Drying Equipment lyophilize and get Nafcillin sodium anhydride 71.5kg, content 93.3%, color and luster is less than No. 3, yellow-green colour.
Above-mentioned Nafcillin sodium anhydride 71.5kg is joined in the acetone soln of 500kg water content 2.8%, temperature raising to 29 ℃ stirring and dissolving, 10 minutes molten clear, add the 1kg gac and stir decolouring 20 minutes, be pressed in the sterilisable chamber crystallizer through carbon removal, degerming, defeathering coordinate filter then, open to stir and be warming up to 2 hours precipitation and crystallizations of 46 ℃ of insulated and stirred, the logical tap water cooling of crystallizer interlayer is 2 hours then, fundatrix liquid is taken off in filtration, filter cake is cold-draw half an hour again, pulverize sabot and go into baking oven, vacuum-drying gets nafcillin sodium-hydrate aseptic powder 65.3kg, content 99.6%.
Embodiment 5.
The 3kg gac is joined in the nafcillin sodium water solution of 270L concentration about 27%, stir the half an hour of decolouring, through taking off the charcoal press filtration, the filtrate special-purpose stainless dish of freeze-drying of packing into, go into the Freeze Drying Equipment lyophilize and get Nafcillin sodium anhydride 71.9kg, content 92.5%, to color and luster less than No. 3, yellow-green colour.
Above-mentioned Nafcillin sodium anhydride 71.9kg is joined in the butanone solution of 700kg water content 1.0%, temperature raising to 25 ℃ stirring and dissolving, 13 minutes molten clear, add the 1kg gac and stir decolouring 20 minutes, be pressed in the sterilisable chamber crystallizer through carbon removal, degerming, defeathering coordinate filter then, open to stir and be warming up to 3 hours precipitation and crystallizations of 47 ℃ of insulated and stirred, the logical tap water cooling of crystallizer interlayer is 2 hours then, fundatrix liquid is taken off in filtration, filter cake is cold-draw half an hour again, pulverize sabot and go into baking oven, vacuum-drying gets nafcillin sodium-hydrate aseptic powder 65.8kg, content 99.7%.
Claims (6)
1. the preparation method of a nafcillin sodium-hydrate is earlier the nafcillin sodium water solution to be prepared the Nafcillin sodium anhydride through lyophilize, again Nafcillin sodium anhydride crystal water on hydration reaction is made nafcillin sodium-hydrate.
2. the preparation method of nafcillin sodium-hydrate according to claim 1, its preparation method may further comprise the steps:
1), be starting raw material with the nafcillin sodium water solution of 20-30wt%, obtained by freeze drying Nafcillin sodium anhydride;
2), Nafcillin sodium anhydride that step 1) is made is dissolved in the organic solvent acetone or butanone that water content is 1.0-3.0wt%, aseptic condition stirs down and is warmed up to 40-50 ℃, adds an amount of crystal seed, insulation reaction 2-3 hour;
3), cooling 1-2 hour, filter, take off mother liquor, after filter cake making beating washing is drained, pulverize, vacuum-drying gets nafcillin sodium-hydrate.
3. the preparation method of nafcillin sodium-hydrate according to claim 1, it is characterized in that step 2) in the consumption of organic solvent be Nafcillin sodium anhydride weight 4-12 doubly, the temperature of organic solvent dissolving Nafcillin sodium anhydride is controlled at 20-33 ℃.
4. the preparation method of nafcillin sodium-hydrate according to claim 3, the consumption that it is characterized in that organic solvent is 8 times of Nafcillin sodium anhydride weight, the temperature of organic solvent dissolving Nafcillin sodium anhydride is controlled at 28-30 ℃.
5. the preparation method of nafcillin sodium-hydrate according to claim 1 is characterized in that step 2) described in the insulation reaction temperature be 44-48 ℃.
6. the preparation method of nafcillin sodium-hydrate according to claim 1 is characterized in that described nafcillin sodium water solution before lyophilize, adds earlier gac processings of decolouring, and obtains filtrate through the filtration of decarbonization filtering device.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011101387520A CN102250120A (en) | 2011-05-26 | 2011-05-26 | Method for preparing nafcillin sodium monohydrate |
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| CN2011101387520A CN102250120A (en) | 2011-05-26 | 2011-05-26 | Method for preparing nafcillin sodium monohydrate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106800565A (en) * | 2016-12-08 | 2017-06-06 | 桂林南药股份有限公司 | A kind of NAF sodium crystal and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3506645A (en) * | 1968-05-03 | 1970-04-14 | American Home Prod | Monohydrate of sodium salt of 6-(2-ethoxy - 1-naphthamido)penicillanic acid and method of preparation |
| CN101330905A (en) * | 2005-11-18 | 2008-12-24 | 赛多斯有限责任公司 | Lyophilization process and products obtained thereby |
| CN101781315A (en) * | 2010-02-09 | 2010-07-21 | 北京紫萌同达科技有限公司 | Synthesizing method of nafcillin sodium-hydrate |
-
2011
- 2011-05-26 CN CN2011101387520A patent/CN102250120A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3506645A (en) * | 1968-05-03 | 1970-04-14 | American Home Prod | Monohydrate of sodium salt of 6-(2-ethoxy - 1-naphthamido)penicillanic acid and method of preparation |
| CN101330905A (en) * | 2005-11-18 | 2008-12-24 | 赛多斯有限责任公司 | Lyophilization process and products obtained thereby |
| CN101781315A (en) * | 2010-02-09 | 2010-07-21 | 北京紫萌同达科技有限公司 | Synthesizing method of nafcillin sodium-hydrate |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106800565A (en) * | 2016-12-08 | 2017-06-06 | 桂林南药股份有限公司 | A kind of NAF sodium crystal and preparation method thereof |
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Application publication date: 20111123 |