The preparation method of oxacillin sodium and oxacillin for inj
Technical field
The invention belongs to the synthetic field of medicine, particularly, provide the preparation method of a kind of oxacillin sodium and oxacillin for inj, oxacillin sodium and oxacillin for inj product by described method preparation also are provided.
Background technology
Oxacillin sodium is with the 6-APA(6-aminopenicillanic acid) be raw material synthetic semisynthetic penicillin, it has the characteristic of acidproof anti-enzyme, be used for the various infection that the penicillin resistant staphylococcus causes, as septicemia, respiratory tract infection, meningitis, soft tissue infection etc., and by the polyinfection due to streptococcus pyogenes or streptococcus pneumoniae and the penicillin resistant staphylococcus, be determined curative effect, little, the low-cost line medicine of toxic side effect clinically, be decided to be national essential drugs in 1998, American Pharmacopeia 24 editions records.The Oxazacillin sodium sterilized raw is white powder or crystalline powder; Odorless or little smelly.Easily molten in water, soluble,very slightly in acetone or butanols, almost insoluble in vinyl acetic monomer or sherwood oil.Its chemical name is: (2S, 5R, 6R)-3, and 3-dimethyl-6-(5-methyl-3-phenyl-4-oxazolyl formamido group)-7-oxo-4-thia-1-azabicyclo [3,2,0] heptane-2-formic acid sodium salt monohydrate, molecular weight is 441.43, structural formula is:
![Figure 107647DEST_PATH_IMAGE001](https://patentimages.storage.googleapis.com/7b/00/af/31b4cf4e36f972/107647DEST_PATH_IMAGE001.png)
The synthetic route of existing oxacillin sodium and concrete condition all are optimized and design under laboratory scale.But in large-scale industry was synthetic, these routes and condition were because the adaptability of the variation of the mass-and heat-transfer condition under extensive, equipment, power consumption, man-hour, cost, stability etc. are many-sided former thereby become inapplicable.From the laboratory scale lab scale stage, to the pilot scale stage of to a certain degree amplifying, carry out the transition to industrial production at last, in order to determine best route of synthesis and reaction conditions, the quantity that feeds intake, the selection of equipment, optimum flow process of mass transport or the like, need a large amount of practices and therefrom sum up experience.This process is the very long process that the technician constantly meets with problem, uses wisdom to deal with problems.A kind of plant-scale oxacillin sodium synthetic method that is suitable for is not also proposed in the art.
The invention provides a kind of synthetic method that is suitable for synthetic oxacillin sodium on the technical scale, by optimization to multiple parameters such as temperature, pH value, ingredient proportions, realized on technical scale, synthesizing oxacillin sodium with high yield, high purity and high stability, and, directly obtain the oxacillin sodium product that can be used for injecting by control to production environment and process.
Summary of the invention
Chemical reaction in the process of the synthetic oxacillin sodium of the present invention is as follows:
1. condensation reaction
2. acidifying is extracted
3. salify crystallization
。
The technological process of production of the present invention is shown in Figure 1.
The invention provides a kind of method of synthetic oxacillin sodium, comprise step:
(1) condensation: in the condensation jar, add pure water, NaHPO
4And NH
4The Cl dissolving adds 6-APA and Ben Jia isoxazole acyl chlorides; Regulate between pH value to 6.5 ~ 7.0, reacted 2 hours, the adding medicinal carbon filtered and obtains filtrate after reaction finished;
(2) acidifying: in souring tank, add the filtrate of N-BUTYL ACETATE and step (1), regulate pH 1.8 ~ 2.0, leave standstill 30 minutes after, lower layer of water is added in the after-souring jar; In the after-souring jar, add N-BUTYL ACETATE, regulate pH 1.7 ~ 2.0, left standstill 30 minutes; Merge once the extracting solution with after-souring, add pure water and stir washing, leave standstill after 30 minutes and discard water layer; Added the medical active carbon decoloring 10 minutes, and filtered and obtain clear liquor;
(3) crystallization: (15 ~ 18%w/w) Sterile Filtrations join in the crystallizer, and distillation dehydration under the vacuum condition carries out crystallization, crystal solution are pressed into to wash brilliant jar of elimination mother liquor afterwards with the clear liquor of step (2) and sodium acetate soln;
(4) wash crystalline substance: behind the filter fundatrix liquid, wash and add propyl carbinol washing 2 times in brilliant jar, filter is done; Add vinyl acetic monomer, soaked 10 minutes, filter is done;
(5) pulverize and pack: will wash the crystal suction loft drier that filter is done, vacuum vibration drying 4 ~ 5 hours; Dry powder is poured Grinding and granulate machine into and is crossed the pulverizing of 40 mesh sieves; Dry powder after pulverizing is packed in the sterilization Aluminum Drum.
Further, in the method for above-mentioned synthetic oxacillin sodium, step (1) is:
(1) condensation: add pure water in the condensation jar, controlled temperature to 26 ~ 28 ℃ add NaHPO then
4And NH
4The Cl dissolving adds 6-APA and Ben Jia isoxazole acyl chlorides; NaOH with 6 mol/L regulates between pH value to 6.5 ~ 7.0, reacts 2 hours, during the reaction process temperature is controlled at 25 ~ 30 ℃, and pH 6.5 ~ 7.0, and reaction finishes the back and adds medicinal carbon, and after-filtration obtained filtrate in 5 ~ 10 minutes.
Further, in the method for above-mentioned synthetic oxacillin sodium, step (2) is:
(2) acidifying: add N-BUTYL ACETATE in a souring tank, the filtrate of step (1) is all added, 10 ~ 15 ℃ of controlled temperature add 6mol/L H
2SO
4, regulate pH 1.8 ~ 2.0, leave standstill 30 minutes after, lower layer of water is added in the after-souring jar; In the after-souring jar, add N-BUTYL ACETATE, add 6mol/L H
2SO
4, regulate pH 1.7 ~ 2.0, left standstill 30 minutes; Merge once the extracting solution with after-souring, add pure water and stir washing, leave standstill after 30 minutes and discard water layer; Added the medical active carbon decoloring 10 minutes, and filtered and obtain clear liquor.
Further, in the method for above-mentioned synthetic oxacillin sodium, step (3) is:
(3) crystallization: (15 ~ 18%w/w) Sterile Filtrations join in the crystallizer, and crystallizer heats with 70 ℃ ~ 75 ℃ hot water, and distillation dehydration under the vacuum condition is added the N-BUTYL ACETATE of Sterile Filtration midway with the clear liquor of step (2) and sodium acetate soln; When crystal solution moisture is reduced to 0.9 ~ 1.10%w/w, stop distillation, crystal solution is pressed into washes brilliant jar of elimination mother liquor.
Further, in the method for above-mentioned synthetic oxacillin sodium, step (4) is:
(4) wash crystalline substance: behind the filter fundatrix liquid, wash in brilliant jar and add propyl carbinol, stirred 20 minutes, with the washing lotion elimination; Add propyl carbinol once more, stir evenly, filter is done; Add vinyl acetic monomer, soaked 10 minutes, filter is done.
Particularly, the invention provides a kind of method of synthetic oxacillin sodium, comprise step:
(1) condensation: add pure water in the condensation jar, controlled temperature to 26 ~ 28 ℃ add NaHPO then
4And NH
4The Cl dissolving adds 6-APA and Ben Jia isoxazole acyl chlorides; NaOH with 6 mol/L regulates between pH value to 6.5 ~ 7.0, reacts 2 hours, during the reaction process temperature is controlled at 25 ~ 30 ℃, and pH 6.5 ~ 7.0, and reaction finishes the back and adds medicinal carbon, and after-filtration obtained filtrate in 5 ~ 10 minutes;
(2) acidifying: add N-BUTYL ACETATE in a souring tank, the filtrate of step (1) is all added, 10 ~ 15 ℃ of controlled temperature add 6mol/L H
2SO
4, regulate pH 1.8 ~ 2.0, leave standstill 30 minutes after, lower layer of water is added in the after-souring jar; In the after-souring jar, add N-BUTYL ACETATE, add 6mol/L H
2SO
4, regulate pH 1.7 ~ 2.0, left standstill 30 minutes; Merge once the extracting solution with after-souring, add pure water and stir washing, leave standstill after 30 minutes and discard water layer; Added the medical active carbon decoloring 10 minutes, and filtered and obtain clear liquor;
(3) crystallization: (15 ~ 18%w/w) Sterile Filtrations join in the crystallizer, and crystallizer heats with 70 ℃ ~ 75 ℃ hot water, and distillation dehydration under the vacuum condition is added the N-BUTYL ACETATE of Sterile Filtration midway with the clear liquor of step (2) and sodium acetate soln; When crystal solution moisture is reduced to 0.9 ~ 1.10%w/w, stop distillation, crystal solution is pressed into washes brilliant jar of elimination mother liquor;
(4) wash crystalline substance: behind the filter fundatrix liquid, wash in brilliant jar and add propyl carbinol, stirred 20 minutes, with the washing lotion elimination; Add propyl carbinol once more, stir evenly, filter is done; Add vinyl acetic monomer, soaked 10 minutes, filter is done;
(5) pulverize and pack: will wash the crystal suction loft drier that filter is done, vacuum vibration drying 4 ~ 5 hours; Dry powder is poured Grinding and granulate machine into and is crossed the pulverizing of 40 mesh sieves; Dry powder after pulverizing is packed in the sterilization Aluminum Drum.
In the method for above-mentioned synthetic oxacillin sodium, wherein the quantity of each composition is as follows in step (1):
Pure water 4200L
6-APA 93kg
Ben Jia isoxazole acyl chlorides 100kg
Na
2HPO
4 17.5kg
NH
4Cl 1.65kg。
In the method for above-mentioned synthetic oxacillin sodium, wherein in step (2), the N-BUTYL ACETATE consumption is 1100 ~ 1200 L during an acidifying, and the N-BUTYL ACETATE consumption is 400 L during after-souring.
In the method for above-mentioned synthetic oxacillin sodium, wherein in step (4): behind the filter fundatrix liquid, wash adding 580 L propyl carbinols in brilliant jar, stirred 20 minutes, with the washing lotion elimination; Add 190 L propyl carbinols once more, stir evenly, filter is done; Add 200 L vinyl acetic monomers, soaked 10 minutes, filter is done.
In the method for above-mentioned synthetic oxacillin sodium, wherein in step (5): described vacuum vibration drying carries out under greater than 0.08 Mpa, vibrational frequency 1000 rpm at 76 ~ 78 ℃, vacuum tightness.
In the method for aforesaid synthetic oxacillin sodium, described oxacillin sodium is an oxacillin for inj.
In the method for synthetic oxacillin sodium of the present invention, improve at the reaction conditions under the extensive synthetic situation of technical grade, by Combinatorial Optimization to multiple parameters such as temperature, pH value, ingredient proportions, thereby obtain a kind of can be in the oxacillin sodium synthetic method of extensive efficient down, steady running, realized on technical scale, synthesizing oxacillin sodium with high yield, high purity and high stability, and, directly obtain the oxacillin sodium product that can be used for injecting by control to production environment and process.
Description of drawings
Accompanying drawing 1 is technological process of production figure of the present invention.
Embodiment
Describe technical scheme of the present invention in detail below in conjunction with specific embodiment, but following embodiment only is used to that principle of the present invention is described and proof about feasibility of the present invention is provided, rather than constitute restriction scope of the present invention.
Synthesizing of embodiment 1 oxacillin sodium.
Condensation
Add purified water 4200L in the condensation jar, controlled temperature to 26 ℃ ~ 27 ℃ drops into 17.5kg Na
2HPO
4And 1.65kg NH
4The Cl dissolving drops into 93kg 6-APA and 100kg acyl chlorides.Add 6mol/L NaOH solution and regulate pH6.5 ~ 7.0, reacted 2 hours.25 ℃ ~ 28 ℃ of control reaction process temperature, pH6.5 ~ 7.0.Reaction finishes, and adds medicinal carbon 3kg, and after-filtration got in souring tank of clear liquor adding in 5 ~ 10 minutes.
Acidifying is extracted
An acidifying: add 1100 ~ 1200L N-BUTYL ACETATE in the souring tank, condensation filtrate is all added, 10 ~ 12 ℃ of controlled temperature begin to add 6mol/LH
2SO
4, regulate pH 1.8 ~ 2.0, leave standstill 30 minutes after, lower layer of water is added in the after-souring jar.
After-souring: in the after-souring jar, add N-BUTYL ACETATE 400L, add 6mol/L H
2SO
4, regulate pH1.7 ~ 2.0, leave standstill 30 minutes after, lower floor's waste water branch is gone to be handled by three wastes station.
Washing: extracting solution squeezed in the after-souring jar merge, add purified water 500L, stir washing with secondary raffinate.After static 30 minutes, lower floor's waste water branch is gone to be handled by three wastes station.
Decolorization filtering: in the after-souring jar, add the 9kg medicinal carbon, decolour 10 minutes, filter to such an extent that clarify extracting solution.
Crystallization
Extracting solution and sodium acetate soln advance crystallizer respectively through Sterile Filtration.According to the extracting solution sum, (strength of solution is 15 ~ 18%w/w) to the sodium acetate soln of 1.2 times of molar weights of adding.Crystallizer heats with 70 ℃ ~ 75 ℃ hot water, distillation dehydration under vacuum condition, and the N-BUTYL ACETATE of a Sterile Filtration is added in the centre.(more than the vacuum tightness 0.09Mpa) liquid moisture to be crystallized drops to 0.90 ~ 1.10%w/w, stops distillation.Crystal solution is pressed into elimination mother liquor in the filtration washing machine (washing brilliant jar).
Wash crystalline substance
Behind the filter fundatrix liquid, wash adding 580L propyl carbinol in brilliant jar, stirred 20 minutes, the washing lotion elimination.Wash adding 190L propyl carbinol in brilliant jar, stir evenly, filter is done.Wash in brilliant jar and be pressed into the 200L vinyl acetic monomer, soaked 10 minutes, filter is done.
Drying and packing
The crystal of will washed filter doing is used the stainless steel cask material-pumping tube after 220 ℃ of sterilization 2h sterilization, the suction loft drier, and vacuum vibration drying 4 ~ 5 hours, 76 ~ 78 ℃ of hot water, vacuum tightness is greater than 0.08Mpa, vibrational frequency 1000rpm.Dry powder covers bung put into dry powder bucket (through 220 ℃ of sterilization 2h) under 100 grades of laminar flows under vibration, moves between granulation.With the outer wall of 75%v/v ethanolic soln wiping bucket, under 100 grades of laminar flows, open bung, pour Grinding and granulate machine into and cross the pulverizing of 40 mesh sieves.Under 100 grades of laminar flows, dry powder packed in the sterilization Aluminum Drum, go into, cover inner cap, enclosing cover, move to and roll between lid by the 5kg/ barreled.Roll the cap seal mouth, stick the label of using to be checked, fill in lot number, net weight, gross weight etc., reach outer parlor, warehouse-in.
Synthesizing of embodiment 2 oxacillin sodiums.
Condensation
Add purified water 4200L in the condensation jar, controlled temperature to 27 ℃ ~ 28 ℃ drops into 17.5kg Na
2HPO
4And 1.65kg NH
4The Cl dissolving drops into 93kg 6-APA and 100kg acyl chlorides.Add 6mol/L NaOH solution and regulate pH6.5 ~ 7.0, reacted 2 hours.28 ℃ ~ 30 ℃ of control reaction process temperature, pH6.5 ~ 7.0.Reaction finishes, and adds medicinal carbon 3kg, and after-filtration got in souring tank of clear liquor adding in 5 ~ 10 minutes.
Acidifying is extracted
An acidifying: add 1100 ~ 1200L N-BUTYL ACETATE in the souring tank, condensation filtrate is all added, 12 ~ 15 ℃ of controlled temperature begin to add 6mol/LH
2SO
4, regulate pH 1.8 ~ 2.0, leave standstill 30 minutes after, lower layer of water is added in the after-souring jar.
After-souring: in the after-souring jar, add N-BUTYL ACETATE 400L, add 6mol/L H
2SO
4, regulate pH1.7 ~ 2.0, leave standstill 30 minutes after, lower floor's waste water branch is gone to be handled by three wastes station.
Washing: extracting solution squeezed in the after-souring jar merge, add purified water 500L, stir washing with secondary raffinate.After static 30 minutes, lower floor's waste water branch is gone to be handled by three wastes station.
Decolorization filtering: in the after-souring jar, add the 9kg medicinal carbon, decolour 10 minutes, filter to such an extent that clarify extracting solution.
Crystallization
Extracting solution and sodium acetate soln advance crystallizer respectively through Sterile Filtration.According to the extracting solution sum, (strength of solution is 15 ~ 18%w/w) to the sodium acetate soln of 1.2 times of molar weights of adding.Crystallizer heats with 70 ℃ ~ 75 ℃ hot water, distillation dehydration under vacuum condition, and the N-BUTYL ACETATE of a Sterile Filtration is added in the centre.(more than the vacuum tightness 0.09Mpa) liquid moisture to be crystallized drops to 0.90 ~ 1.10%w/w, stops distillation.Crystal solution is pressed into elimination mother liquor in the filtration washing machine (washing brilliant jar).
Wash crystalline substance
Behind the filter fundatrix liquid, wash adding 580L propyl carbinol in brilliant jar, stirred 20 minutes, the washing lotion elimination.Wash adding 190L propyl carbinol in brilliant jar, stir evenly, filter is done.Wash in brilliant jar and be pressed into the 200L vinyl acetic monomer, soaked 10 minutes, filter is done.
Drying and packing
The crystal of will washed filter doing is used the stainless steel cask material-pumping tube after 220 ℃ of sterilization 2h sterilization, the suction loft drier, and vacuum vibration drying 4 ~ 5 hours, 76 ~ 78 ℃ of hot water, vacuum tightness is greater than 0.08Mpa, vibrational frequency 1000rpm.Dry powder covers bung put into dry powder bucket (through 220 ℃ of sterilization 2h) under 100 grades of laminar flows under vibration, moves between granulation.With the outer wall of 75%v/v ethanolic soln wiping bucket, under 100 grades of laminar flows, open bung, pour Grinding and granulate machine into and cross the pulverizing of 40 mesh sieves.Under 100 grades of laminar flows, dry powder packed in the sterilization Aluminum Drum, go into, cover inner cap, enclosing cover, move to and roll between lid by the 5kg/ barreled.Roll the cap seal mouth, stick the label of using to be checked, fill in lot number, net weight, gross weight etc., reach outer parlor, warehouse-in.
The detection of embodiment 3 quality producies.
Utilize to detect the conventional sense method of semi-synthetic penicillins medicine, each product of 3 batches that embodiment 1 and embodiment 2 are made detects, and average yield reaches 93.0%, and the quality examination result is as follows: