CN103159782B - The method of extracting penicillin and the extracting method of application and penicillin thereof from benzylpenicillin sodium solution - Google Patents
The method of extracting penicillin and the extracting method of application and penicillin thereof from benzylpenicillin sodium solution Download PDFInfo
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Abstract
The invention provides a kind of method and application thereof of extracting penicillin from benzylpenicillin sodium solution, the method comprises and being mixed with benzylpenicillin sodium solution by organic solvent, obtain the first mixture, and make the pH value of described first mixture for being less than 6, described first mixture is divided into oil phase and aqueous phase, separates described oil phase, to obtain the extraction liquid containing penicillin, wherein, described organic solvent is sec-butyl acetate.Present invention also offers a kind of extracting method of penicillin.Higher penicillin g extract yield can be obtained according to method of the present invention.Further, sec-butyl acetate has lower production cost, thus can reduce the production cost of penicillin according to method of the present invention.In addition, because the toxicity of sec-butyl acetate is lower, therefore the impact for operator ' s health can be reduced according to method of the present invention.
Description
Technical field
The present invention relates to a kind of method of extracting penicillin from benzylpenicillin sodium solution, and the method is extracting the application in penicillin from penicillin fermentation liquid; The invention still further relates to a kind of extracting method of penicillin.
Background technology
Penicillin is the general name that a class has the material of 6-aminopenicillanic acid parent nucleus, and according to substituent difference, penicillin mainly comprises penicillin-f, penicillin G, p-hydroxybenzylpenicillin, penicillin K, penicillin v, penbritin and amoxycillin.Parent nucleus 6-aminopenicillanic acid due to penicillin is a kind of acid, and therefore, under sour environment, penicillin is the penicillinic acid being soluble in hydrophobic organic solvent; Under alkaline environment, penicillin then becomes salt soluble in water.The solvability that the solvent extraction extracting penicillin from penicillin fermentation liquid utilizes penicillin different under acid or alkali environment just, extracts penicillin and carries out purifying from penicillin fermentation liquid.
At present, the normally used solvent extraction extracting penicillin from penicillin fermentation liquid comprises: the solution adding acid in penicillin fermentation liquid, and be that acid penicillin fermentation liquid mixes with n-butyl acetate by this, thus penicillin is transferred in n-butyl acetate, obtain the extraction liquid containing penicillin and n-butyl acetate; The pH value containing the extraction liquid of penicillin and n-butyl acetate obtained is adjusted to alkalescence, and mix with water, thus penicillin is converted into the salt of penicillin soluble in water and the salt of this penicillin is transferred in aqueous phase, obtain the penicillin Aqueous extracts of the salt containing described penicillin; In above-mentioned penicillin Aqueous extracts, add propyl carbinol, and carry out component distillation at reduced pressure conditions, remove propyl carbinol and water, the salt-pepper noise of penicillin is separated out, and drying and obtain the solid product of the salt of penicillin.In addition, also can repeat above-mentioned extraction step, thus improve the purity of the salt of penicillin further.
But the extraction yield of existing penicillin menstruum extraction process needs to improve further.
Summary of the invention
The object of the invention is to the deficiency overcoming prior art existence, provide a kind of from benzylpenicillin sodium solution, extract the method for penicillin and the extracting method of penicillin, high according to the extraction yield of method of the present invention.
The present inventor is surprised to find that in research process, if adopt sec-butyl acetate to replace n-butyl acetate to carry out extracting penicillin from benzylpenicillin sodium solution as solvent, can significantly improve the extraction yield of penicillin.
The invention provides a kind of method of extracting penicillin from benzylpenicillin sodium solution, the method comprises and being mixed with benzylpenicillin sodium solution by organic solvent, obtain the first mixture, and make the pH value of described first mixture for being less than 6, described first mixture is divided into oil phase and aqueous phase, separates described oil phase, to obtain the extraction liquid containing penicillin, wherein, described organic solvent is sec-butyl acetate.
Present invention also offers a kind of method according to the present invention from penicillin fermentation liquid, extract the application in penicillin.
Invention further provides a kind of extracting method of penicillin, the method comprises:
(1) organic solvent is mixed with benzylpenicillin sodium solution, obtain the first mixture, and make the pH value of described first mixture for being less than 6, described first mixture is divided into oil phase and aqueous phase, separate described oil phase, to obtain the extraction liquid containing penicillin, wherein, described organic solvent is sec-butyl acetate;
(2) water is mixed with the described extraction liquid containing penicillin, obtain the second mixture, and make the pH value of described second mixture be more than 6, described second mixture is divided into oil phase and aqueous phase, separate described aqueous phase, to obtain the extraction liquid of the salt containing penicillin; And
(3) extraction liquid of the described salt containing penicillin is mixed with propyl carbinol, obtain the 3rd mixture, and described 3rd mixture is carried out distillation and concentration under component distillation condition, the salt-pepper noise of the penicillin in the concentrated solution obtained is separated out, to obtain the salt of the penicillin for solid.
Use sec-butyl acetate as the organic solvent extracting penicillin from benzylpenicillin sodium solution according to method of the present invention, higher extraction yield can be obtained.Further, due to compared with n-butyl acetate, the production cost of sec-butyl acetate is lower, therefore can reduce the production cost of penicillin according to method of the present invention.In addition, because the toxicity of sec-butyl acetate is lower, therefore the impact for operator ' s health can also be reduced according to method of the present invention.
Embodiment
The invention provides a kind of method of extracting penicillin from benzylpenicillin sodium solution, the method comprises and being mixed with benzylpenicillin sodium solution by organic solvent, obtain the first mixture, and make the pH value of described first mixture for being less than 6, described first mixture is divided into oil phase and aqueous phase, separates described oil phase, to obtain the extraction liquid containing penicillin, wherein, described organic solvent is sec-butyl acetate.
According to the present invention, described penicillin can be various take 6-aminopenicillanic acid as parent nucleus, and 6-aminopenicillanic acid has the penicillin of different substituents.Such as, described penicillin can be penicillin G or penicillin v.
According to the present invention, described benzylpenicillin sodium solution can be the benzylpenicillin sodium solution in various source, such as: described benzylpenicillin sodium solution can for being undertaken the penicillin fermentation liquid obtained by bacterial fermentation processes filtering and the optional concentrated and aqueous solution containing penicillin that obtains.Particularly, described benzylpenicillin sodium solution can for be undertaken the fermented liquid adopting thread fungus three grade fermemtation technique or spherical bacterium second order fermentation technique to obtain filtering and the optional concentrated and aqueous solution containing penicillin that obtains.According to the present invention, the method of being carried out filtering by described penicillin fermentation liquid can be selected for the routine of this area, as long as mycelium remaining in described penicillin fermentation liquid and albumen can be removed, such as: first can add flocculation agent to make albumen precipitation in fermented liquid out in described penicillin fermentation liquid, then carry out filtering or carrying out Plate Filtration with vacuum drum.
Method of the present invention is not particularly limited for the content of penicillin in described benzylpenicillin sodium solution, can be that the routine of this area is selected, such as: in described benzylpenicillin sodium solution, the content of penicillin can be 0.1-4.5 % by weight.
Adopt sec-butyl acetate as the organic solvent of extracting penicillin from benzylpenicillin sodium solution according to the method for extracting penicillin from benzylpenicillin sodium solution of the present invention.The present inventor surprisingly finds in research process, and compared with the n-butyl acetate being conventionally used as solvent, the solubleness of penicillin in sec-butyl acetate is higher.Under identical extraction conditions, the percentage extraction of sec-butyl acetate to penicillin is higher.
Therefore, according to method of the present invention, when all the other conditions are identical, compared with carrying out extracting penicillin with use n-butyl acetate, adopt sec-butyl acetate can obtain higher penicillin g extract yield as organic solvent; In other words, compared with carrying out extracting penicillin with use n-butyl acetate, the sec-butyl acetate of less amount can be used to obtain identical penicillin g extract yield according to method of the present invention.
In the present invention, described extraction yield refers to that being extracted material after extraction system reaches balance enters the per-cent being extracted the total amount of material in amount in extraction liquid (comprise exist with molecular species be extracted material) and original liquid, obtained by following formulae discovery
Extraction yield (% by weight)=be extracted material enters total amount × 100% being extracted material in the amount/original liquid in extraction liquid.
Further, compared with n-butyl acetate, the toxicity of sec-butyl acetate is lower, thus higher according to the security of method of the present invention, and the harm produced operator ' s health is less.Such as: in the dangerous kinds of goods database of security production supervision and management office of Shandong Province, the maximum concentration of n-butyl acetate in operating environment should more than 700 milligram/cubic metre, and the maximum concentration of sec-butyl acetate in operating environment then can reach 950 milligrams/cubic metre; In addition, according to the data in the dangerous kinds of goods database of security production supervision and management office of Shandong Province, the medium lethal dose (rat oral, 96 hours) of sec-butyl acetate is 13400 mg/kg, and the medium lethal dose of n-butyl acetate is then 10768 mg/kg.
In addition, compared with n-butyl acetate, the production cost of sec-butyl acetate is lower, thus, uses sec-butyl acetate to carry out the production cost that extracting penicillin can also reduce penicillin.
According to the present invention, the volume ratio of sec-butyl acetate and benzylpenicillin sodium solution can be the conventional amount used of this area, such as: 1: 1.5-5.According to the present invention, from the extraction yield of balance penicillin and the angle of the consumption of reduction organic solvent, the volume ratio of sec-butyl acetate and benzylpenicillin sodium solution is preferably 1: 2-4.According to the method for extracting penicillin from benzylpenicillin sodium solution of the present invention, the method mix sec-butyl acetate with benzylpenicillin sodium solution and condition are not particularly limited, and can be ordinary method and the typical conditions of this area.
Usually, the time mixed with benzylpenicillin sodium solution by sec-butyl acetate can be 0.1-10 minute, is preferably 1-5 minute; The temperature of mixing can be 0-10 DEG C, is preferably 2-6 DEG C.
Method according to the present invention comprises makes the pH value of described first mixture for being less than 6.When the pH value of described first mixture is for being less than 6, the penicillin in described first mixture exists as the acid, thus can move to oil phase from aqueous phase, to obtain the extraction liquid containing penicillin.According to the present invention, preferably make the pH value of described first mixture be 1.8-3.0, more preferably make the pH value of described first mixture be 2.0-2.8.
According to the present invention, the method for well known to a person skilled in the art can be adopted to make the pH value of described first mixture meet above-mentioned requirements.Such as, can by adding acid in described benzylpenicillin sodium solution, thus make the pH value of described first mixture for being less than 6, being preferably 1.8-3.0, being more preferably 2.0-2.8; Can also by adding acid in described first mixture, thus make the pH value of described first mixture for being less than 6, being preferably 1.8-3.0, being more preferably 2.0-2.8.According to the present invention, described acid can be the conventional various acid in this area, such as: described acid can one or more for being selected from sulfuric acid, hydrochloric acid, phosphoric acid and oxalic acid.
PH value is that described first mixture being less than 6 is divided into oil phase and aqueous phase by the various methods that this area can be adopted to commonly use, and isolates oil phase, thus obtains the extraction liquid (that is, the oil phase containing penicillin) containing penicillin.Such as: can be that the first mixture being less than 6 is divided into oil phase and aqueous phase by pH value by centrifugal separation method or standing separation method, and by separation of oil out.
The extraction liquid containing penicillin obtained by method of the present invention can process according to concrete application scenario, thus obtains the penicillin into solid.Such as, can by being contacted with precipitation agent (as sodium-acetate-ethanol) by described penicillin g extract liquid, thus make penicillium crystallization out; Also can utilize the penicillin characteristic that solubleness is minimum in aqueous when iso-electric point, the pH value of the described extraction liquid containing penicillin is adjusted to iso-electric point, make penicillin Precipitation; Can also by the described extraction liquid containing penicillin be mixed in the basic conditions with water, thus penicillin is transferred in water with the form of the salt of penicillin from sec-butyl acetate, and the aqueous solution of the salt containing described penicillin is carried out decompression co-boiling distiling, thus obtain the salt of the penicillin into solid.
Of the present invention from benzylpenicillin sodium solution the method for extracting penicillin be specially adapted to by penicillin fermentation liquid after filtration and optional concentrated and extracting penicillin in the benzylpenicillin sodium solution that obtains.Thus, present invention also offers a kind of method of the present invention from penicillin fermentation liquid, extract the application in penicillin.
Invention further provides a kind of extracting method of penicillin, the method comprises:
(1) organic solvent is mixed with benzylpenicillin sodium solution, obtain the first mixture, and make the pH value of described first mixture for being less than 6, described first mixture is divided into oil phase and aqueous phase, separate described oil phase, to obtain the extraction liquid containing penicillin, wherein, described organic solvent is sec-butyl acetate;
(2) water is mixed with the described extraction liquid containing penicillin, obtain the second mixture, and make the pH value of described second mixture be more than 6, described second mixture is divided into oil phase and aqueous phase, separate described aqueous phase, to obtain the extraction liquid of the salt containing penicillin; And
(3) extraction liquid of the described salt containing penicillin is mixed with propyl carbinol, obtain the 3rd mixture, and described 3rd mixture is carried out distillation and concentration under component distillation condition, the salt-pepper noise of the penicillin in the concentrated solution obtained is separated out, to obtain the salt of the penicillin for solid.
Use sec-butyl acetate carrys out the penicillin in the extracting penicillin aqueous solution as organic solvent, be described in detail, do not repeat them here with the method obtaining the extraction liquid containing penicillin above.
Object of the present invention is realized according to the method for extracting penicillin from benzylpenicillin sodium solution that the extracting method of penicillin of the present invention is the application of the invention, for the extraction liquid of the salt obtained containing penicillin and be not particularly limited by the condition that distillation and concentration makes the salt of penicillin crystallize out from the extraction liquid of the described salt containing penicillin, it can be the routine selection of this area.
According to the extracting method of penicillin of the present invention, the volume ratio of water and the described extraction liquid containing penicillin can be 1: 2-4.
Comprising according to the extracting method of penicillin of the present invention makes the pH value of described second mixture be more than 6.Be under the condition of more than 6 in pH value, penicillin exists with the form of water-soluble salt, thus can move in aqueous phase from oil phase, thus obtain the aqueous phase of the salt containing penicillin.According to the present invention, the pH value of described second mixture is preferably made to be 6.8-7.4.
According to the extracting method of penicillin of the present invention, the method that this area can be adopted to commonly use meets above-mentioned requirements to make the pH value of described second mixture.Such as, can by making the pH value of described second mixture be more than 6, be preferably 6.8-7.4 containing adding in the extraction liquid of penicillin containing the aqueous solution being selected from the alkaline matters such as sodium bicarbonate, bicarbonate of ammonia, sodium hydroxide, sodium carbonate and ammoniacal liquor to described; Also can by being added to by above-mentioned alkaline matter for mixing to prepare in the water of described second mixture with the described extraction liquid containing penicillin, thus the pH value of the second mixture obtained be made to be more than 6, to be preferably 6.8-7.4.
According to the extracting method of penicillin of the present invention, the various methods that this area can be adopted to commonly use by pH value be more than 6 described second mixture be divided into oil phase and aqueous phase, and separate described aqueous phase, to obtain the extraction liquid (that is, the aqueous phase of the salt containing penicillin) of the salt containing penicillin.Such as: described second mixture that can be more than 6 by pH value by centrifugal separation method or standing separation method is divided into oil phase and aqueous phase, and then separates described aqueous phase.
According to the extracting method of penicillin of the present invention, propyl carbinol and the described volume ratio containing the extraction liquid of the salt of penicillin are not particularly limited.Preferably, the volume ratio of the extraction liquid of propyl carbinol and the described salt containing penicillin can be 1.8-2.5: 1, is preferably 2.0-2.5: 1.
Be not particularly limited for the described extraction liquid of salt containing penicillin and the mixture of propyl carbinol being carried out the condition that component distillation concentrates according to the extracting method of penicillin of the present invention, as long as water and propyl carbinol can steam with the form of azeotrope by described component distillation condition, thus make the salt-pepper noise of the penicillin in concentrated solution separate out.Such as: described component distillation condition can comprise: temperature is 16-26 DEG C, pressure is 0.67-1.3kPa.
From the angle of the purity of the penicillin of raising preparation further, can also comprise according to the extracting method of penicillin of the present invention and the salt of the penicillin obtained is dissolved in the water, be carry out extracting the extraction fluid obtained containing penicillin with sec-butyl acetate under the condition being less than 6 in pH value, and be with water, described extraction fluid is extracted under the condition of more than 6 in pH value, obtain the extraction fluid of the salt containing penicillin, and distill under component distillation condition after the extraction fluid of the salt containing penicillin is mixed with propyl carbinol, thus obtain the salt of the penicillin into solid.
Namely, can also comprise according to the extracting method of penicillin of the present invention and the salt of described penicillin is carried out following operation at least one times: the salt (as sodium salt or sylvite) of penicillin is dissolved in the water by (1), obtain the aqueous solution of the salt containing described penicillin, the pH value of the described aqueous solution is adjusted to and is less than 6, be that the aqueous solution being less than 6 mixes with sec-butyl acetate by this pH value, obtain 4 mixture, described 4 mixture is divided into oil phase and aqueous phase, and isolate oil phase, to obtain extraction fluid containing penicillin (namely, oil phase containing penicillin), (2) the described extraction fluid containing penicillin is mixed with water, obtain the 5th mixture, and make the pH value of described 5th mixture be adjusted to more than 6, described 5th mixture is divided into oil phase and aqueous phase, and isolate aqueous phase, to obtain the extraction fluid (that is, the aqueous phase of the salt containing penicillin) of the salt containing penicillin, and the extraction fluid of the described salt containing penicillin mixes with propyl carbinol by (3), and carry out distillation and concentration under component distillation condition, the salt-pepper noise of the penicillin in the concentrated solution obtained is separated out, to obtain the salt of the penicillin for solid.According to the present invention, in step (1), the salt of described penicillin and the weight ratio of water can be 1: 2-4, are preferably 1: 2-3.Condition in above-mentioned each step operation can be identical with previously described condition, repeats no more herein.
The present invention is described in detail below in conjunction with embodiment.
Embodiment 1
The present embodiment is used for illustrating according to method of the present invention and application thereof.
(1) in penicillin thread fungus fermented liquid, pentadecyl bromination pyridine and oxalic acid is added (wherein, the consumption of pentadecyl bromination pyridine is 6g, the add-on of oxalic acid makes the pH value of fermented liquid be 5) carry out pre-treatment, and carry out Plate Filtration, obtain 400mL benzylpenicillin sodium solution (with the total amount of described benzylpenicillin sodium solution for benchmark, the content of penicillin is 3.5 % by weight).Described penicillin thread fungus fermented liquid is prepared by the following method:
Chrysogenum is inoculated on solid medium, at the temperature of 25 DEG C, cultivates 7-10 days, obtain penicillium spores culture.Spore cultures to be made in inoculation of suspension liquid to seeding tank in sterilized substratum with sterilized water, pass into sterile air, stirring, 28h is cultivated at the temperature of 27 DEG C, then seed culture fluid is inoculated into fermentor tank sterilized containing in the substratum of toluylic acid precursor, pass into sterile air, stir, cultivate 7 days at the temperature of 27 DEG C, obtain penicillin fermentation liquid.Fill into toluylic acid precursor and appropriate substratum during the fermentation.
(2) dilute sulphuric acid that concentration is 10 % by weight is added in the 400mL benzylpenicillin sodium solution obtained to step (1), the pH value of benzylpenicillin sodium solution is adjusted to 2.0, then with 126mL sec-butyl acetate at the temperature of 5 DEG C, mix 1 minute, and adopt high speed centrifugation method that said mixture is divided into oil phase and aqueous phase, and isolate oil phase, thus the sec-butyl acetate solution obtained containing penicillin, extraction yield is 83.18%, and in extracting phase, the content of sec-butyl acetate is 0.5 % by weight.
(3) the sec-butyl acetate solution containing penicillin step (2) obtained mixes 5 minutes with sodium bicarbonate aqueous solution (pH the is 7.8) volume ratio with 4: 1 at the temperature of 5 DEG C, the pH value of the mixture obtained is 6.8, and adopt high speed centrifugation separation method that said mixture is divided into oil phase and aqueous phase, isolate aqueous phase, thus obtain the aqueous solution of the salt containing penicillin.
(4) aqueous solution and the propyl carbinol of the salt containing penicillin step (3) obtained mix 2 minutes with the volume ratio of 1: 2.5 at 10 DEG C, the mixture obtained is carried out component distillation, wherein, the condition of component distillation comprises: temperature is 16 DEG C, and pressure is 0.67kPa.In still-process, water and propyl carbinol form azeotrope and are distilled out of, the salt then crystallization of penicillin.The crystal obtained is carried out wash and drying, obtain the penicillin salt that 10.9g is solid.
Comparative example 1
The method identical with embodiment 1 is adopted to extract penicillin from benzylpenicillin sodium solution, unlike, in step (2), n-butyl acetate is used to replace sec-butyl acetate, obtain the n-butyl acetate solution containing penicillin, extraction yield is 79.06%, and in extracting phase, the content of n-butyl acetate is 0.9 % by weight; Finally obtain the penicillin salt that 10.2g is solid.
Comparative example 2
The method identical with embodiment 1 is adopted to extract penicillin from penicillin fermentation liquid, unlike, in step (2), 150mL n-butyl acetate is used to replace 126mL sec-butyl acetate, n-butyl acetate solution containing penicillin, extraction yield is 79.56%, and in extracting phase, the content of n-butyl acetate is 0.9 % by weight; Finally obtain the penicillin salt that 10.3g is solid.
Comparative example 3
The method identical with embodiment 1 is adopted to extract penicillin from penicillin fermentation liquid, unlike, in step (2), tert.-butyl acetate is used to replace sec-butyl acetate, obtain the tert.-butyl acetate solution containing penicillin, extraction yield is 79.02%, and in extracting phase, the content of tert.-butyl acetate is 0.7 % by weight; Finally obtain the penicillin salt that 10.2g is solid.
Embodiment 2
The present embodiment is used for illustrating according to method of the present invention and application thereof.
(1) in penicillin thread fungus fermented liquid, pentadecyl bromination pyridine and oxalic acid is added (wherein, the consumption of pentadecyl bromination pyridine is 6g, the add-on of oxalic acid makes the pH value of fermented liquid be 5.2) carry out pre-treatment, and carry out Plate Filtration, obtain 350mL benzylpenicillin sodium solution (with the total amount of described benzylpenicillin sodium solution for benchmark, the content of penicillin is 3.8 % by weight).Described penicillin thread fungus fermented liquid is prepared by the following method:
Chrysogenum is inoculated on solid medium, at the temperature of 25 DEG C, cultivates 7-10 days, penicillium spores culture can be obtained.Spore to be made in inoculation of suspension liquid to seeding tank in sterilized substratum with sterilized water, pass into sterile air, stirring, 24h is cultivated at the temperature of 27 DEG C, then seed culture fluid is inoculated into fermentor tank sterilized containing in the substratum of toluylic acid precursor, pass into sterile air, stir, cultivate 7 days at the temperature of 27 DEG C, obtain penicillin fermentation liquid.Fill into toluylic acid precursor and appropriate substratum during the fermentation.
(2) dilute sulphuric acid that concentration is 10 % by weight is added in the 350mL benzylpenicillin sodium solution obtained to step (1), the pH value of benzylpenicillin sodium solution is adjusted to 2.2, then with 233mL sec-butyl acetate at the temperature of 6 DEG C, mix 2 minutes, and adopt high speed centrifugation method that said mixture is divided into oil phase and aqueous phase, isolate oil phase, thus the sec-butyl acetate solution obtained containing penicillin, extraction yield is 85.10%, and in extracting phase, the content of sec-butyl acetate is 0.52 % by weight.
(3) the sec-butyl acetate solution containing penicillin step (2) obtained mixes 5 minutes with sodium bicarbonate aqueous solution (pH the is 8.2) volume ratio with 3: 1 at the temperature of 10 DEG C, the pH value of the mixture obtained is 7.0, and adopt high speed centrifugation method that the mixture obtained is divided into oil phase and aqueous phase, isolate aqueous phase, thus obtain the aqueous solution of the salt containing penicillin.
(4) aqueous solution and the propyl carbinol of the salt containing penicillin step (3) obtained mix 3 minutes with the volume ratio of 1: 2.2 at 5 DEG C, the mixture obtained is carried out component distillation, wherein, the condition of component distillation comprises: temperature is 20 DEG C, and pressure is 0.8kPa.In still-process, water and propyl carbinol form azeotrope and are distilled out of, the salt then crystallization of penicillin.After the crystal obtained is carried out washing and drying, obtain the salt that 10.4g is the penicillin of solid.
Embodiment 3
The present embodiment is used for illustrating according to method of the present invention and application thereof.
The method identical with embodiment 2 is adopted to extract penicillin from penicillin fermentation liquid, unlike, in step (2), use 175mL sec-butyl acetate, obtain the sec-butyl acetate solution containing penicillin, extraction yield is 84.36%, and in extracting phase, the content of sec-butyl acetate is 0.5 % by weight; Finally obtain the salt that 10.3g is the penicillin of solid.
Embodiment 4
The present embodiment is used for illustrating according to method of the present invention and application thereof.
(1) in penicillin thread fungus fermented liquid, pentadecyl bromination pyridine and oxalic acid is added (wherein, the consumption of pentadecyl bromination pyridine is 6g, the add-on of oxalic acid makes the pH value of fermented liquid be 5.1) carry out pre-treatment, and carry out Plate Filtration, obtain 750mL benzylpenicillin sodium solution (with the total amount of described benzylpenicillin sodium solution for benchmark, the content of penicillin is 4.0 % by weight).Described penicillin thread fungus fermented liquid is prepared by the following method:
Chrysogenum is inoculated on solid medium, at the temperature of 25 DEG C, cultivates 7-10 days, penicillium spores culture can be obtained.Spore to be made in inoculation of suspension liquid to seeding tank in sterilized substratum with sterilized water, pass into sterile air, stirring, 26h is cultivated at the temperature of 27 DEG C, then seed culture fluid is inoculated into fermentor tank sterilized containing in the substratum of toluylic acid precursor, pass into sterile air, stir, cultivate 7 days at the temperature of 27 DEG C, obtain penicillin fermentation liquid.Fill into toluylic acid precursor and appropriate substratum during the fermentation.
(2) dilute sulphuric acid that concentration is 10 % by weight is added in the 750mL benzylpenicillin sodium solution obtained to step (1), the pH value of benzylpenicillin sodium solution is adjusted to 2.8, then with 150mL sec-butyl acetate mixture at the temperature of 2 DEG C, mix 3 minutes, and adopt high speed centrifugation method that said mixture is divided into oil phase and aqueous phase, isolate oil phase, thus the sec-butyl acetate solution obtained containing penicillin, extraction yield is 80.12%, and in extracting phase, the content of sec-butyl acetate is 0.45 % by weight.
(3) the sec-butyl acetate solution containing penicillin step (2) obtained mixes 2 minutes with sodium bicarbonate aqueous solution (pH the is 8.6) volume ratio with 2: 1 at the temperature of 5 DEG C, the pH value of the mixture obtained is 7.4, and adopt high speed centrifugation method that the mixture obtained is divided into oil phase and aqueous phase, isolate aqueous phase, thus obtain the aqueous solution of the salt containing penicillin.
(4) by the aqueous solution and the propyl carbinol of the salt containing penicillin obtained with 1: 2.5 volume ratio at the temperature of 4 DEG C, mix 5 minutes, the mixture obtained is carried out component distillation, wherein, the condition of component distillation comprises: temperature is 25 DEG C, and pressure is 1.2kPa.In still-process, water and propyl carbinol form azeotrope and are distilled out of, the salt then crystallization of penicillin.After the crystal obtained carries out washing rear drying, obtain the salt that 22.2g is the penicillin of solid.
Embodiment 5
The present embodiment is used for illustrating according to method of the present invention and application thereof.
The method identical with embodiment 4 is adopted to extract penicillin from penicillin fermentation liquid, unlike, in step (2), use 187.5mL sec-butyl acetate, obtain the sec-butyl acetate solution containing penicillin, extraction yield is 80.69%, and in extracting phase, the content of sec-butyl acetate is 0.45 % by weight; Finally obtain the salt that 22.3g is the penicillin of solid.
Claims (10)
1. the method for an extracting penicillin from benzylpenicillin sodium solution, the method comprises and being mixed with benzylpenicillin sodium solution by organic solvent, obtain the first mixture, and make the pH value of described first mixture be 1.8-3.0, described first mixture is divided into oil phase and aqueous phase, separates described oil phase, to obtain the extraction liquid containing penicillin, it is characterized in that, described organic solvent is sec-butyl acetate, and the volume ratio of sec-butyl acetate and described benzylpenicillin sodium solution is 1:1.5-5.
2. method according to claim 1, wherein, the volume ratio of sec-butyl acetate and described benzylpenicillin sodium solution is 1:2-4.
3. the method described in claim 1 or 2 is extracting the application in penicillin from penicillin fermentation liquid.
4. an extracting method for penicillin, the method comprises:
(1) organic solvent is mixed with benzylpenicillin sodium solution, obtain the first mixture, and make the pH value of described first mixture be 1.8-3.0, described first mixture is divided into oil phase and aqueous phase, separate described oil phase, to obtain the extraction liquid containing penicillin, wherein, described organic solvent is sec-butyl acetate, and the volume ratio of sec-butyl acetate and described benzylpenicillin sodium solution is 1:1.5-5;
(2) water is mixed with the described extraction liquid containing penicillin, obtain the second mixture, and make the pH value of described second mixture be more than 6, described second mixture is divided into oil phase and aqueous phase, separate described aqueous phase, to obtain the extraction liquid of the salt containing penicillin; And
(3) extraction liquid of the described salt containing penicillin is mixed with propyl carbinol, obtain the 3rd mixture, and described 3rd mixture is carried out distillation and concentration under component distillation condition, the salt-pepper noise of the penicillin in the concentrated solution obtained is separated out, to obtain the salt of the penicillin for solid.
5. method according to claim 4, wherein, the volume ratio of sec-butyl acetate and described benzylpenicillin sodium solution is 1:2-4.
6. the method according to claim 4 or 5, wherein, described benzylpenicillin sodium solution obtains by being carried out filtering by penicillin fermentation liquid; Or by penicillin fermentation liquid is successively carried out filtering and concentrating obtaining.
7. method according to claim 4, wherein, the volume ratio of water and the described extraction liquid containing penicillin is 1:2-4.
8. method according to claim 4, wherein, makes the pH value of described second mixture be 6.8-7.4.
9. method according to claim 4, wherein, the volume ratio of the extraction liquid of propyl carbinol and the described salt containing penicillin is 1.8-2.5:1.
10. method according to claim 4, wherein, described component distillation condition comprises: temperature is 16-26 DEG C, and pressure is 0.67-1.3kPa.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1191221A (en) * | 1997-12-31 | 1998-08-26 | 华北制药股份有限公司 | Process for one-shot crystallization of sodium penicillin |
| CN1232034A (en) * | 1999-04-02 | 1999-10-20 | 清华大学 | Process for direct preparing penicillin sodium salt from fermentation liquid |
| CN1263097A (en) * | 2000-01-11 | 2000-08-16 | 亓平言 | Technological process for extracting penicillin from fermented filtrate |
| WO2007063107A1 (en) * | 2005-12-02 | 2007-06-07 | Dsm Ip Assets B.V. | Process for the preparation of a potassium salt of penicillin |
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2011
- 2011-12-08 CN CN201110404961.5A patent/CN103159782B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1191221A (en) * | 1997-12-31 | 1998-08-26 | 华北制药股份有限公司 | Process for one-shot crystallization of sodium penicillin |
| CN1232034A (en) * | 1999-04-02 | 1999-10-20 | 清华大学 | Process for direct preparing penicillin sodium salt from fermentation liquid |
| CN1263097A (en) * | 2000-01-11 | 2000-08-16 | 亓平言 | Technological process for extracting penicillin from fermented filtrate |
| WO2007063107A1 (en) * | 2005-12-02 | 2007-06-07 | Dsm Ip Assets B.V. | Process for the preparation of a potassium salt of penicillin |
Non-Patent Citations (1)
| Title |
|---|
| 青霉素钠萃取工艺的优化;王聪;《河北化工》;20080920;第31卷(第9期);第40-41页 * |
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| CN103159782A (en) | 2013-06-19 |
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