CN102718780A - Preparation method of cefmetazole sodium - Google Patents
Preparation method of cefmetazole sodium Download PDFInfo
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- CN102718780A CN102718780A CN2011101583189A CN201110158318A CN102718780A CN 102718780 A CN102718780 A CN 102718780A CN 2011101583189 A CN2011101583189 A CN 2011101583189A CN 201110158318 A CN201110158318 A CN 201110158318A CN 102718780 A CN102718780 A CN 102718780A
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Abstract
The invention discloses a preparation method of cefmetazole sodium, comprising the following steps: (1) dissolving phosphorus pentachloride in dichloromethane, then adding cyanomethylthio potassium acetate to prepare a side-chain acyl chloride solution; dissolving 7-MAC in dichloromethane, and adding organic base and the above side-chain acyl chloride solution to wash to obtain a cefmetazole benzyl ester solution; (2) adding the cefmetazole benzyl ester solution in an aluminum trichloride anisole solution, washing, regulating the pH value to 6.0-9.0, crystallizing, filtering and drying to obtain cefmetazole amine salt; and (3) dissolving the cefmetazole amine salt in an organic solvent solution, adding cation exchange resin, removing the cation exchange resin by filtration, regulating the pH to 5-8, then removing the organic solvent by distillation at reduced pressure, letting the residual cefmetazole sodium solution be subject to decoloration and aseptic filtration, and then directly conducting freeze-drying to obtain cefmetazole sodium. The method is simple and practicable and has the advantages of high yield, good quality and low cost.
Description
Technical field:
The present invention relates to a kind of preparation method of cefmetazole sodium, belong to cephalosporin compound preparation field in the medicine synthesis technique.
Background technology:
Cefmetazole sodium; Its English name is Cefmetazole sodium; Chemical name is: (6R, 7S)-7-[[2-(cyanogen methyl sulphur) acetyl] amino]-7-methoxyl group-3-[(1-methyl tetrazolium-5-yl) thiomethyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid sodium salt, molecular formula: C15H16N7NaO5S3; Molecular weight: 493.52, structural formula:
Cefmetazole sodium is a second generation cephalosporin; Wide spectrum-lactamase that negative bacillus is produced has stability preferably; Negative bacillus such as intestinal bacteria, Cray uncle pneumobacillus, Proteus mirabilis, shigella element, salmonellin have susceptibility preferably to these article; Gold Portugal bacterium, A organize Hemolytic streptococcus, catarrh Bradley Chinese bacterium is extremely sensitive to these article; Bacteroide fragilis is had better antibacterial activity, and enterochelin, Rhodopseudomonas, methicillin-resistant gold Portugal bacterium, streptococcus pneumoniae, meningococcus be insensitive or resistance to these article.Be used for responsive microbial respiratory system infection, biliary tract infection, urinary system infection, Obstetric and Gynecologic Department infectation of bacteria, skin soft-tissue infection and operation back preventing infection clinically.
Chinese patent 200910014972.5 discloses a kind of cefmetazole sodium compound and preparation method thereof; With 7 beta-aminos-7 α-methoxyl group-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-3-cephem-4-carboxylic acid benzhydryl ester and cyanogen methyl sulphur sodium acetate hybrid reaction under the condition that Tosyl chloride exists; Generate cefmetazole acid, add sodium hydroxide and make cefmetazole sodium.This method has been used highly basic sodium hydroxide, causes impurity too much, and content is on the low side, and color is dark partially.Chinese patent 201010116167.6 discloses a kind of preparation method of cefmetazole sodium; Generate cefmetazole benzyl ester with 7 beta-aminos-7 α-methoxyl group-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-3-cephem-4-carboxylic acid benzhydryl ester and cyanogen first sulfydryl Acetyl Chloride 98Min.; Take off the benzyl ester with the iron trichloride diethyl ether solution and obtain cefmetazole acid; Change into cefmetazole sodium with sodium hydrogencarbonate again, yield reaches 58-62%, and product purity has only 92%.Chinese patent 201010100852.X discloses a kind of process for purification of cefmetazole sodium, and the cefmetazole sodium compound is through acid-base reaction, macroporous adsorbent resin and charcoal absorption; Reach the purpose of purifying, increased production stage, cause total recovery to reduce; Behind the absorption with macroporous adsorbent resin cefmetazole; With a large amount of solvent wash-outs, aftertreatment is complicated, has increased production cost greatly.
At present, cefmetazole sodium production of raw medicine yield is on the low side, and purity is not high, and production process is complicated, and the solvent consumption is very big, therefore, is necessary to seek a kind of simple, and yield is high, the measured preparation method of matter.
Summary of the invention:
The objective of the invention is to overcome the deficiency of above-mentioned prior art and provide a kind of simple, yield is high, the preparation method of the cefmetazole sodium that quality is good, cost is low.
Purpose of the present invention can reach through following measure: a kind of preparation method of cefmetazole sodium is characterized in that it comprises the steps:
(1), the preparation of cefmetazole benzyl ester:
A, phosphorus pentachloride is dissolved in methylene dichloride is made into the solution that concentration is 10-20wt%, cool to-1 ℃--4 ℃, add cyanogen first Thiovanic acid potassium, temperature control stirs 1-1.5h for 10 ± 2 ℃, makes the side chain solution of acid chloride;
B, 7-MAC is dissolved in methylene dichloride is made into the solution that concentration is 10-20wt%; Be cooled to-50--10 ℃, add organic bases and above-mentioned side chain solution of acid chloride, behind ℃ of--30 ℃ stirring reaction 1-2h of temperature control-40; Dilute hydrochloric acid solution (3-10%W/V) collection that adds 5-10 times of (W/V) volume of 7-MAC is washed once; Organic phase uses sodium-chlor dilute solution (5-10%W/V) collection of 5-10 times of (W/V) volume of 7-MAC to wash once again, abandons water, gets cefmetazole benzyl ester solution;
(2), the preparation of cefmetazole amine salt:
A, cool under methyl-phenoxide stirred-10-10 ℃, slowly add the aluminum chloride methyl-phenoxide solution that aluminum chloride is processed 30-50wt%;
B, with above-mentioned cefmetazole benzyl ester solution, cool to-40--20 ℃, stir and to add above-mentioned aluminum chloride methyl-phenoxide solution down; Reaction 1-2h, hydrolysis finishes, and adds Hydrogen chloride and acetone mixed solution collection and washes; Organic phase uses 3-8% (W/V) sodium chloride solution collection to wash again; The organic phase adding organic amine adjusting PH that is rich in cefmetazole acid is 6.0-9.0, cooling-5-5 ℃ of stirred crystallization 4-8h, filtration, the dry cefmetazole amine salt that gets;
(3), the preparation of cefmetazole sodium:
Above-mentioned cefmetazole amine salt is dissolved in the organic solvent aqueous solution of 3-6 times (W/V); Cool to the 10-20 degree; Add the doubly Zeo-karb stirring 1-6h of (W/W) of 2-5, the filtering Zeo-karb, filtrating uses sodium ion alkali to transfer PH to be 5-8; Remove organic solvent again under reduced pressure, remaining cefmetazole sodium water solution through decolouring, after the sterile filtration directly freeze-drying obtain cefmetazole sodium.
In order further to realize the object of the invention, cyanogen first Thiovanic acid potassium and phosphorus pentachloride mass ratio are 1 among described step (1)/a: 1.0-1.5.
In order further to realize the object of the invention, 7-MAC and cyanogen first Thiovanic acid potassium weight ratio are 1 among described step (1)/b: 0.3-0.7; Organic bases is triethylamine or pyridine, and the mass ratio of organic bases and 7-MAC is 0.5-1: 1.
In order further to realize the object of the invention, aluminum chloride and 7-MAC weight ratio are 0.85-0.88 among described step (2)/a: 1.
In order further to realize the object of the invention, the organic amine among described step (2)/b is for generating amine salt with cefmetazole acid, and the amine salt that generates is insoluble to all organic amines of methylene dichloride.
In order further to realize the object of the invention, described organic amine is dicyclohexyl amine, N.N-dibenzyl-ethylenediamin diacetate (DBED), pentanoic, Diisopropylamine, N-tertiary butyl hexahydroaniline.
In order further to realize the object of the invention, the Hydrogen chloride among described step (2)/b and the hydrochloric acid that consists of volume ratio 37%W/V of acetone mixed solution: purified water: acetone=1: 15: 20, mixeding liquid volume and 7-MAC weight ratio=15-20: 1.The sodium chloride solution volume of 3-8%W/V and 7-MAC weight ratio=10-15: 1.
In order further to realize the object of the invention, the organic solvent aqueous solution is aqueous acetone solution, aqueous ethanolic solution, methanol aqueous solution in the described step (3), one or more mixing in the own nitrile aqueous solution, the ETHYLE ACETATE aqueous solution, the tetrahydrofuran aqueous solution.
In order further to realize the object of the invention, the volume ratio of the organic solvent aqueous solution is a purified water in the described step (3): solvent=100: 25-150.
In order further to realize the object of the invention, Zeo-karb is a strongly acidic cationic exchange resin in the described step (3).
In order further to realize the object of the invention, the sodium ion alkali in the said step (3) is one or more mixing in sodium hydroxide, yellow soda ash, the sodium hydrogencarbonate.
Chemical equation of the present invention is following:
A kind of preparation method of cefmetazole sodium is characterized in that it comprises the steps:
(1), the preparation of cefmetazole benzyl ester:
A, phosphorus pentachloride is dissolved in methylene dichloride is made into the solution that concentration is 10-20wt%, cool to-1 ℃--4 ℃, add cyanogen first Thiovanic acid potassium, temperature control stirs 1-1.5h for 10 ± 2 ℃, makes the side chain solution of acid chloride;
B, 7-MAC is dissolved in methylene dichloride is made into the solution that concentration is 10-20wt%; Be cooled to-50--10 ℃, add organic bases and above-mentioned side chain solution of acid chloride, behind ℃ of--30 ℃ stirring reaction 1-2h of temperature control-40; Dilute hydrochloric acid solution (3-10%W/V) collection that adds 5-10 times of (W/V) volume of 7-MAC is washed once; Organic phase uses sodium-chlor dilute solution (5-10%W/V) collection of 5-10 times of (W/V) volume of 7-MAC to wash once again, abandons water, gets cefmetazole benzyl ester solution;
(2), the preparation of cefmetazole amine salt:
A, cool under methyl-phenoxide stirred-10-10 ℃, slowly add the aluminum chloride methyl-phenoxide solution that aluminum chloride is processed 30-50wt%;
B, with above-mentioned cefmetazole benzyl ester solution, cool to-40--20 ℃, stir and to add above-mentioned aluminum chloride methyl-phenoxide solution down; Reaction 1-2h, hydrolysis finishes, and adds Hydrogen chloride and acetone mixed solution collection and washes; Organic phase uses 3-8% (W/V) sodium chloride solution collection to wash again; The organic phase adding organic amine adjusting PH that is rich in cefmetazole acid is 6.0-9.0, cooling-5-5 ℃ of stirred crystallization 4-8h, filtration, the dry cefmetazole amine salt that gets;
(3), the preparation of cefmetazole sodium:
Above-mentioned cefmetazole amine salt is dissolved in the organic solvent aqueous solution of 3-6 times (W/V); Cool to the 10-20 degree; Add the doubly Zeo-karb stirring 1-6h of (W/W) of 2-5, the filtering Zeo-karb, filtrating uses sodium ion alkali to transfer PH to be 5-8; Remove organic solvent again under reduced pressure, remaining cefmetazole sodium water solution through decolouring, after the sterile filtration directly freeze-drying obtain cefmetazole sodium.
In order further to realize the object of the invention, cyanogen first Thiovanic acid potassium and phosphorus pentachloride mass ratio are 1 among described step (1)/a: 1.0-1.5.
In order further to realize the object of the invention, 7-MAC and cyanogen first Thiovanic acid potassium weight ratio are 1 among described step (1)/b: 0.3-0.7; Organic bases is triethylamine or pyridine, and the mass ratio of organic bases and 7-MAC is 0.5-1: 1.
In order further to realize the object of the invention, aluminum chloride and 7-MAC weight ratio are 0.85-0.88 among described step (2)/a: 1.
In order further to realize the object of the invention; The organic phase that is rich in cefmetazole acid among described step (2)/b adds organic amine; This organic amine is for generating amine salt with cefmetazole acid; And the amine salt that generates is insoluble to all organic amines of methylene dichloride, preferred dicyclohexyl amine, N.N-dibenzyl-ethylenediamin diacetate (DBED), pentanoic, Diisopropylamine, N-tertiary butyl hexahydroaniline, more first-selected dicyclohexyl amine.Hydrogen chloride and acetone mixed solution consist of volume ratio 37%W/V hydrochloric acid: purified water: acetone=1: 15: 20, mixeding liquid volume and 7-MAC weight ratio=15-20: 1; 3-8%W/V sodium chloride solution volume and 7-MAC weight ratio=10-15: 1.
In order further to realize the object of the invention; The organic solvent aqueous solution is aqueous acetone solution, aqueous ethanolic solution, methanol aqueous solution in the described step (3); One or more mixing in the own nitrile aqueous solution, the ETHYLE ACETATE aqueous solution, the tetrahydrofuran aqueous solution, preferred aqueous acetone solution.
In order further to realize the object of the invention, the volume ratio of the organic solvent aqueous solution is a purified water in the described step (3): solvent=100: 25-150.
In order further to realize the object of the invention, Zeo-karb is a strongly acidic cationic exchange resin in the described step (3).Preferred 732 strongly acidic cationic exchange resins.In order further to realize the object of the invention, the sodium ion alkali in the said step (3) is one or more mixing in sodium hydroxide, yellow soda ash, the sodium hydrogencarbonate.Preferred sodium hydrogencarbonate.
The present invention compares with prior art can produce following positively effect: the present invention is through adding organic amine in being rich in the extraction liquid of cefmetazole acid; Cefmetazole is separated out with cefmetazole amine salt mode; Avoided cefmetazole acid crystalline difficulty from water; Reduce cefmetazole acid residual quantity in the mother liquor, improved yield.Cefmetazole amine salt stable in properties, placement, drying process are difficult for degraded, have guaranteed the quality raising, and cefmetazole forms the process of amine salt, also is the process of a purification, further improves the quality of products.The cefmetazole amine salt is dissolved in the organic solvent aqueous solution, adds strong acidic ion resin exchange absorption amine ion, filters; Filtrating changes into cefmetazole sodium with sodium ion alkali, and underpressure distillation goes out organic solvent, and direct freeze-drying obtains aseptic cefmetazole sodium after remaining cefmetazole sodium water solution decolouring, the sterile filtration; Its process is simple; Mild condition simultaneously also can absorbed portion impurity, quality is improved also beneficial.Preparing method's gross weight yield of the present invention can reach more than 72%, and product gas purity reaches more than 99.5%.
Embodiment:
Below in conjunction with specific embodiment, further specify the present invention, should be understood that embodiment only be used to the present invention is described and be not used in the restriction scope of the present invention.Should be understood that in addition those skilled in the art can do various changes or modification to the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within claims that the application pays institute restricted portion equally.
Embodiment 1:
(1) preparation of cefmetazole benzyl ester:
A, methylene dichloride 400ml add 40gPCL5, cool to-1 ℃, add 40g cyanogen first Thiovanic acid potassium, and temperature control stirs 1h for 8 ℃, and it is subsequent use to make cyanogen first sulfydryl chloride solution.
B, methylene dichloride 665ml add the 7-MAC (another name methoxy cephalo) of 133g, cool to-50 ℃, add the 66.5g pyridine, drip the cyanogen first sulfydryl chloride solution among a, and 1h is stirred in-40 ℃ of reactions.Add the Hydrogen chloride agitator treating phase-splitting of 3% (W/V) of 1330ml, abandon water, organic phase adds the NaCL agitator treating phase-splitting of 5% (W/V) of 1330ml again, abandons water, and it is subsequent use to get U.S. azoles benzyl ester dichloromethane solution.
(2) preparation of cefmetazole amine salt
A, the 376.83g methyl-phenoxide stirred down cool to-10 ℃, stir and time slowly add the methyl-phenoxide solution for standby that the 113.05g aluminum chloride is processed.
B, with U.S. azoles benzyl ester dichloromethane solution, cool to-40 ℃, stir and to add the good aluminum chloride methyl-phenoxide solution of above-prepared down; Temperature control-40 ℃ reaction 1h, hydrolysis finishes, and adds the 37% hydrochloric acid agitator treating of 600ml water+800ml acetone+40ml; Leave standstill, phase-splitting, organic phase adds 3% (W/V) NaCL solution stirring of 800ml again, leaves standstill, phase-splitting; Discard water; It is 6.0 that the organic phase stirring adds dicyclohexyl amine adjusting PH down ,-5 ℃ of stirred crystallization 4h that lower the temperature, filtration, the dry cefmetazole dicyclohexyl amine salt that gets.
(3) preparation of cefmetazole sodium
Cefmetazole dicyclohexyl amine salt is dissolved in the mixed solution of the own nitrile aqueous solution and the ETHYLE ACETATE aqueous solution, the volume of this mixed aqueous solution is 3 times of cefmetazole dicyclohexyl amine salt weight, cools to 10 ℃; The 732 wet Zeo-karbs that add 2 times of weight of cefmetazole dicyclohexyl amine salt; Stir 6h, filter, it is 5 that filtrating uses sodium hydroxide to transfer PH; Remove organic solvent again under reduced pressure, remaining cefmetazole sodium water solution through decolouring, after the sterile filtration directly freeze-drying obtain cefmetazole sodium.
Embodiment 2:
(1) preparation of cefmetazole benzyl ester
A, methylene dichloride 300ml add the PCL5 of 60g, cool to-3 ℃, add 60g cyanogen first Thiovanic acid potassium, and temperature control stirs 1.5h for 12 ℃, and it is subsequent use to make cyanogen first sulfydryl chloride solution.
B, methylene dichloride 1200ml add the 7-MAC of 120g, cool to-10 ℃, add the 120g triethylamine, drip cyanogen first sulfydryl chloride solution, and 2h is stirred in-30 ℃ of reactions.Add 10% (W/V) hydrochloric acid agitator treating phase-splitting of 600ml, abandon water, organic phase adds the NaCL agitator treating phase-splitting of 10% (W/V) of 600ml again, abandons water, and it is subsequent use to get U.S. azoles benzyl ester dichloromethane solution.
(2) preparation of cefmetazole amine salt
A, the 211.2g methyl-phenoxide stirred down cool to 10 ℃, stir and time slowly add the methyl-phenoxide solution for standby that the 105.6g aluminum chloride is processed.
B, with U.S. azoles benzyl ester dichloromethane solution, cool to-20 ℃, stir and to add the good aluminum chloride methyl-phenoxide solution of above-prepared down; Temperature control-20 ℃ reaction 2h, hydrolysis finishes, and adds 37% (W/V) hydrochloric acid agitator treating of 750ml water+1000ml acetone+50ml; Leave standstill, phase-splitting, organic phase adds 8% (W/V) NaCL solution stirring of 1440ml again, leaves standstill, phase-splitting; Discard water; It is 9.0 that the organic phase stirring adds N.N-dibenzyl-ethylenediamin diacetate (DBED) adjusting PH down, the 5 ℃ of stirred crystallization 8h that lower the temperature, filtration, the dry cefmetazole DBED amine salt that gets.
(3) preparation of cefmetazole sodium:
Cefmetazole DBED amine is dissolved in the tetrahydrofuran aqueous solution, and the volume of this aqueous solution is 6 times of cefmetazole DBED amine salt weight, cools to 20 ℃; The Zeo-karb that adds 5 times of weight of cefmetazole DBED amine salt; Stir 1h, filter, it is 8 that filtrating uses sodium hydroxide to transfer PH; Remove organic solvent again under reduced pressure, remaining cefmetazole sodium water solution through decolouring, after the sterile filtration directly freeze-drying obtain cefmetazole sodium.
Embodiment 3:
(1) preparation of cefmetazole benzyl ester
A, methylene dichloride 588ml add the PCL5 of 84g, cool to-4 ℃, add 56g cyanogen first Thiovanic acid potassium, and temperature control stirs 1.2h for 10 ℃, and it is subsequent use to make cyanogen first sulfydryl chloride solution.
B, methylene dichloride 600ml add the 7-MAC (another name methoxy cephalo) of 80g, cool to-30 ℃, add the 50g pyridine; Drip cyanogen first sulfydryl chloride solution, 1.5h is stirred in-35 ℃ of reactions, adds 8% (W/V) hydrochloric acid agitator treating phase-splitting of 560ml; Abandon water; Organic phase adds the NaCL agitator treating phase-splitting of 8% (W/V) of 640ml again, abandons water, and it is subsequent use to get U.S. azoles benzyl ester dichloromethane solution.
(2) preparation of cefmetazole amine salt
A, the 172g methyl-phenoxide stirred down cool to 0 ℃, stir and time slowly add the methyl-phenoxide solution for standby that the 68.8g aluminum chloride is processed.
B, with U.S. azoles benzyl ester dichloromethane solution, cool to-30 ℃, stir and to add the good aluminum chloride methyl-phenoxide solution of above-prepared down; Temperature control-30 ℃ reaction 1.5h, hydrolysis finishes, and adds 37% (W/V) hydrochloric acid agitator treating of 666ml water+888ml acetone+44.4ml; Leave standstill, phase-splitting, organic phase adds 5% (W/V) NaCL solution stirring of 1200ml again, leaves standstill, phase-splitting; Discard water; It is 7.0 that the organic phase stirring adds pentanoic adjusting PH down, the 0 ℃ of stirred crystallization 6h that lowers the temperature, filtration, the dry cefmetazole hexichol amine salt that gets.
(3) preparation of cefmetazole sodium
Cefmetazole hexichol amine salt is dissolved in the mixed solution of aqueous ethanolic solution, and the volume of this mixed aqueous solution is 4 times of cefmetazole hexichol amine salt weight, cools to 15 ℃; The 732 wet Zeo-karbs that add 3 times of weight of cefmetazole hexichol amine salt; Stir 3h, filter, it is 6 that filtrating uses sodium hydroxide to transfer PH; Remove organic solvent again under reduced pressure, remaining cefmetazole sodium water solution through decolouring, after the sterile filtration directly freeze-drying obtain cefmetazole sodium.
Embodiment 4:
(1) preparation of cefmetazole benzyl ester:
A, methylene dichloride 400ml add 40gPCL5, cool to-2 ℃, add 40.3g cyanogen first Thiovanic acid potassium, and temperature control stirs 1h for 8 ℃, and it is subsequent use to make cyanogen first sulfydryl chloride solution.
B, methylene dichloride 400ml add 80g7-MAC (another name methoxy cephalo), cool to-50 ℃, add the 40g pyridine, drip the cyanogen first sulfydryl chloride solution among a, and 1h is stirred in-40 ℃ of reactions.Add the 37% hydrochloric acid agitator treating phase-splitting of 735ml water+65ml, abandon water, organic phase adds 800ml water+40gNaCL agitator treating phase-splitting again, abandons water, and it is subsequent use to get U.S. azoles benzyl ester dichloromethane solution.
(2) preparation of cefmetazole amine salt
A, the 140g methyl-phenoxide stirred down cool to-10 ℃, stir and time slowly add the methyl-phenoxide solution for standby that the 70g aluminum chloride is processed.
B, with U.S. azoles benzyl ester dichloromethane solution, cool to-40 ℃, stir and to add the good aluminum chloride methyl-phenoxide solution of above-prepared down; Temperature control-40 ℃ reaction 1h, hydrolysis finishes, and adds 666ml water+890ml acetone+45ml37% hydrochloric acid agitator treating; Leave standstill, phase-splitting, organic phase adds 1200ml water+36gNaCL again and stirs, and leaves standstill, phase-splitting; Discard water; It is 6.0 that the organic phase stirring adds Diisopropylamine adjusting PH down ,-5 ℃ of stirred crystallization 4h that lower the temperature, filtration, the dry 85g cefmetazole diisopropyl amine salt that gets.
(3) preparation of cefmetazole sodium
85g cefmetazole diisopropyl amine salt is dissolved in 200ml water for injection+64ml acetone, cools to 10 ℃, adds wet 732 Zeo-karbs (water cut 50%) of 176g, stirs 6h; Filter, filtrating is transferred PH5 with solid sodium bicarbonate, underpressure distillation acetone, and temperature control is below 25 ℃; Drain acetone, added the 3g activated carbon decolorizing again 30 minutes, filter, 20ml injection washing charcoal; Merging filtrate, washing lotion, through aseptic membrane filtration, freeze-drying obtains the 61g cefmetazole sodium.
Embodiment 5:
(1) preparation of cefmetazole benzyl ester
A, methylene dichloride 300ml add 60gPCL5, cool to-2 ℃, add 40.3g cyanogen first Thiovanic acid potassium, and temperature control stirs 1.5h for 12 ℃, and is subsequent use.
B, methylene dichloride 800ml add 80g7-MAC, cool to-10 ℃, add the 80g triethylamine, drip a cyanogen first sulfydryl chloride solution, and 2h is stirred in-30 ℃ of reactions.Add 292ml water+108ml37% hydrochloric acid agitator treating phase-splitting, abandon water, organic phase adds 400ml water+40gNaCL agitator treating phase-splitting again, abandons water, and it is subsequent use to get U.S. azoles benzyl ester dichloromethane solution.
(2) preparation of cefmetazole amine salt
A, the 230g methyl-phenoxide stirred down cool to 10 ℃, stir and time slowly add the methyl-phenoxide solution for standby that the 70g aluminum chloride is processed.
B, with U.S. azoles benzyl ester dichloromethane solution, cool to-20 ℃, stir and to add the good aluminum chloride methyl-phenoxide solution of above-prepared down; Temperature control-20 ℃ reaction 2h, hydrolysis finishes, and adds 500ml water+666ml acetone+33ml 37% hydrochloric acid agitator treating; Leave standstill, phase-splitting, organic phase adds 800ml water+64gNaCL again and stirs, and leaves standstill, phase-splitting; Discard water; It is 9.0 that the organic phase stirring adds N-tertiary butyl hexahydroaniline adjusting PH down, the 5 ℃ of stirred crystallization 8h that lower the temperature, filtration, the dry 90g cefmetazole N-tertiary butyl cyclohexylamine salt that gets.
(3) preparation of cefmetazole sodium
94g cefmetazole N-tertiary butyl cyclohexylamine salt is dissolved in 226ml water for injection+338ml methyl alcohol, cools to 20 ℃, adds wet 732 Zeo-karbs (water cut 50%) of 470g, stirs 1h; Filter, filtrating is transferred PH8 with solid sodium carbonate, underpressure distillation methyl alcohol, and temperature control is below 25 ℃; Drain methyl alcohol, added the 3g activated carbon decolorizing again 30 minutes, filter, 30ml injection washing charcoal; Merging filtrate, washing lotion, through aseptic membrane filtration, freeze-drying obtains the 59g cefmetazole sodium.
Embodiment 6:
(1) preparation of cefmetazole benzyl ester
A, methylene dichloride 350ml add 50gPCL5, cool to-2 ℃, add 40.3g cyanogen first Thiovanic acid potassium, and temperature control stirs 1h for 10 ℃, and is subsequent use.
B, methylene dichloride 600ml add 80g7-MAC (another name methoxy cephalo), cool to-30 ℃, add the 50g pyridine, drip a cyanogen first sulfydryl chloride solution, and 1.5h is stirred in-40 ℃ of reactions.Add 600ml water+80ml 37% hydrochloric acid agitator treating phase-splitting, abandon water, organic phase adds 600ml water+48gNaCL agitator treating phase-splitting again, abandons water, and it is subsequent use to get U.S. azoles benzyl ester dichloromethane solution.
(2) preparation of cefmetazole amine salt
A, the 170g methyl-phenoxide stirred down cool to 0 ℃, stir and time slowly add the methyl-phenoxide solution for standby that the 70g aluminum chloride is processed.
B, with U.S. azoles benzyl ester dichloromethane solution, cool to-30 ℃, stir and to add the good aluminum chloride methyl-phenoxide solution of above-prepared down; Temperature control-30 ℃ reaction 1.5h, hydrolysis finishes, and adds 415ml water+555ml acetone+28ml 37% hydrochloric acid agitator treating; Leave standstill, phase-splitting, organic phase adds 1000ml water+55gNaCL again and stirs, and leaves standstill, phase-splitting; Discard water; It is 7.0 that the organic phase stirring adds dicyclohexyl amine adjusting PH down, the 0 ℃ of stirred crystallization 6h that lowers the temperature, filtration, the dry 86g cefmetazole dicyclohexyl amine salt that gets.
(3) preparation of cefmetazole sodium
86g cefmetazole dicyclohexyl amine salt is dissolved in 150ml water for injection+200ml acetone, cools to 15 ℃, adds wet 732 Zeo-karbs (water cut 50%) of 300g, stirs 3h; Filter, filtrating is transferred PH6.5 with solid sodium bicarbonate, underpressure distillation acetone, and temperature control is below 25 ℃; Drain acetone, added the 3g activated carbon decolorizing again 30 minutes, filter, 20ml injection washing charcoal; Merging filtrate, washing lotion, through aseptic membrane filtration, freeze-drying obtains the 60g cefmetazole sodium.
Claims (11)
1. the preparation method of a cefmetazole sodium is characterized in that it comprises the steps:
(1), the preparation of cefmetazole benzyl ester:
A, phosphorus pentachloride is dissolved in methylene dichloride is made into the solution that concentration is 10-20wt%, cool to-1 ℃--4 ℃, add cyanogen first Thiovanic acid potassium, temperature control stirs 1-1.5h for 10 ± 2 ℃, makes the side chain solution of acid chloride;
B, 7-MAC is dissolved in methylene dichloride is made into the solution that concentration is 10-20wt%; Be cooled to-50--10 ℃, add organic bases and above-mentioned side chain solution of acid chloride, behind ℃ of--30 ℃ stirring reaction 1-2h of temperature control-40; Dilute hydrochloric acid solution (3-10%W/V) collection that adds 5-10 times of (W/V) volume of 7-MAC is washed once; Organic phase uses sodium-chlor dilute solution (5-10%W/V) collection of 5-10 times of (W/V) volume of 7-MAC to wash once again, abandons water, gets cefmetazole benzyl ester solution;
(2), the preparation of cefmetazole amine salt:
A, cool under methyl-phenoxide stirred-10-10 ℃, slowly add the aluminum chloride methyl-phenoxide solution that aluminum chloride is processed 30-50wt%;
B, with above-mentioned cefmetazole benzyl ester solution, cool to-40-20 ℃, stir and add above-mentioned aluminum chloride methyl-phenoxide solution down; Reaction 1-2h, hydrolysis finishes, and adds Hydrogen chloride and acetone mixed solution collection and washes; Organic phase uses 3-8% (W/V) sodium chloride solution collection to wash again; The organic phase adding organic amine adjusting PH that is rich in cefmetazole acid is 6.0-9.0, cooling-5-5 ℃ of stirred crystallization 4-8h, filtration, the dry cefmetazole amine salt that gets;
(3), the preparation of cefmetazole sodium:
Above-mentioned cefmetazole amine salt is dissolved in the organic solvent aqueous solution of 3-6 times (W/V); Cool to the 10-20 degree; Add the doubly Zeo-karb stirring 1-6h of (W/W) of 2-5, the filtering Zeo-karb, filtrating uses sodium ion alkali to transfer PH to be 5-8; Remove organic solvent again under reduced pressure, remaining cefmetazole sodium water solution through decolouring, after the sterile filtration directly freeze-drying obtain cefmetazole sodium.
2. the preparation method of a kind of cefmetazole sodium according to claim 1 is characterized in that cyanogen first Thiovanic acid potassium and phosphorus pentachloride mass ratio are 1 among described step (1)/a: 1.0-1.5.
3. the preparation method of a kind of cefmetazole sodium according to claim 1 is characterized in that 7-MAC and cyanogen first Thiovanic acid potassium weight ratio are 1 among described step (1)/b: 0.3-0.7; Organic bases is triethylamine or pyridine, and the mass ratio of organic bases and 7-MAC is 0.5-1: 1.
4. the preparation method of a kind of cefmetazole sodium according to claim 1 is characterized in that aluminum chloride and 7-MAC weight ratio are 0.85-0.88 among described step (2)/a: 1.
5. the preparation method of a kind of cefmetazole sodium according to claim 1 it is characterized in that organic amine among described step (2)/b for generating amine salt with cefmetazole acid, and the amine salt that generates is insoluble to all organic amines of methylene dichloride.
6. the preparation method of a kind of cefmetazole sodium according to claim 5 is characterized in that described organic amine is dicyclohexyl amine, N.N-dibenzyl-ethylenediamin diacetate (DBED), pentanoic, Diisopropylamine, N-tertiary butyl hexahydroaniline.
7. the preparation method of a kind of cefmetazole sodium according to claim 1; It is characterized in that Hydrogen chloride and the hydrochloric acid that consists of volume ratio 37%W/V of acetone mixed solution among described step (2)/b: purified water: acetone=1: 15: 20, mixeding liquid volume and 7-MAC weight ratio=15-20: 1.The sodium chloride solution volume of 3-8%W/V and 7-MAC weight ratio=10-15: 1.
8. the preparation method of a kind of cefmetazole sodium according to claim 1; It is characterized in that the organic solvent aqueous solution is aqueous acetone solution, aqueous ethanolic solution, methanol aqueous solution in the described step (3), one or more mixing in the own nitrile aqueous solution, the ETHYLE ACETATE aqueous solution, the tetrahydrofuran aqueous solution.
9. the preparation method of a kind of cefmetazole sodium according to claim 1 is characterized in that the volume ratio of the organic solvent aqueous solution in the described step (3) is a purified water: solvent=100: 25-150.
10. the preparation method of a kind of cefmetazole sodium according to claim 1 is characterized in that Zeo-karb is a strongly acidic cationic exchange resin in the described step (3).
11. the preparation method of a kind of cefmetazole sodium according to claim 1 is characterized in that the sodium ion alkali in the said step (3) is one or more mixing in sodium hydroxide, yellow soda ash, the sodium hydrogencarbonate.
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| CN108752216A (en) * | 2018-07-20 | 2018-11-06 | 重庆天地药业有限责任公司 | A kind of high purity N, the environment-friendly preparation method thereof of N`- dibenzyl-ethylenediamin diacetates |
| CN109232610A (en) * | 2018-09-04 | 2019-01-18 | 华北制药河北华民药业有限责任公司 | A kind of refining methd of cefonicid dibenzylethylenediamsalt salt |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104557978A (en) * | 2014-12-31 | 2015-04-29 | 重庆福安药业(集团)股份有限公司 | Preparation method for cefmetazole sodium |
| CN104557978B (en) * | 2014-12-31 | 2017-07-18 | 重庆福安药业(集团)股份有限公司 | A kind of preparation method of cefmetazole sodium |
| CN108752216A (en) * | 2018-07-20 | 2018-11-06 | 重庆天地药业有限责任公司 | A kind of high purity N, the environment-friendly preparation method thereof of N`- dibenzyl-ethylenediamin diacetates |
| CN109232610A (en) * | 2018-09-04 | 2019-01-18 | 华北制药河北华民药业有限责任公司 | A kind of refining methd of cefonicid dibenzylethylenediamsalt salt |
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