CN101054386A - Method of synthesizing cefuroxime - Google Patents
Method of synthesizing cefuroxime Download PDFInfo
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- CN101054386A CN101054386A CN 200610054593 CN200610054593A CN101054386A CN 101054386 A CN101054386 A CN 101054386A CN 200610054593 CN200610054593 CN 200610054593 CN 200610054593 A CN200610054593 A CN 200610054593A CN 101054386 A CN101054386 A CN 101054386A
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Abstract
The invention relates to medicine synthesis technology field, especially a cefuroxime sodium synthesis method. The method is: selectively hydrolyzing 7-aminocephalosporanic acid (7-ACA) with alkali liquor to obtain 3- deacetylated 7-amido-cephalosporanic acid (7-DACA), then condensing with[cis]-2-[2- furyl]-2-[ methoxy imino] acetyl chloride to obtain 3- decarbamoyl cefuroxime (DCCF), transforming 3-methylol of 3- decarbamoyl cefuroxime (DCCF) with chlorosulfonyl Isocyanate (CSI)to obtain cefuroxime, then treating with sodium iso-octoate to obtain cefuroxime sodium crude product, employing dilution crystallization method for refining cefuroxime sodium crude product to obtain final product. The quality of final product accords with 'Chinese Pharmacopoeia' 2005 edition. The inventive method is simply operated and material is easily obtained. The final product yield is high which is easy for industrial production.
Description
Invention field
The invention belongs to the synthetic field of medicine; be specifically related to Cefuroxime sodium (Cefuroxime sodium) promptly (6R, 7R)-7-[[2-furans (suitable-methoxyimino) ethanoyl] amino]-the new synthetic method of 3-carbamyl yloxymethyl cephalo-3-alkene-4-carboxylic acid sodium.
Technical background
Since U.S. E.Lilly in 1964 exploitation cefoxitin, cynnematin family antibiotic listing kind is from four generations of the first-generation to the kind surplus in the of 50 nearly.Wherein many kinds were once much-vaunted, but along with Time fleets past overshadowed gradually, and cephalofruxin is all the time clinically in occupation of critical role.
Cefuroxime sodium is the semi-synthetic cynnematin of the s-generation of efficient, safety, wide spectrum, great majority are produced the pathogenic microbial infection of β-Nei Xiananmei remarkable curative effect is arranged, be that Britain Glaxo company took the lead in developing listing in 1975, " Chinese pharmacopoeia 2005 editions and " American Pharmacopeia " 29 editions all record, and are present clinical application one of cephalosporin analog antibiotics the most widely.
The structural formula of Cefuroxime sodium following (I):
7 alpha-carbon atoms of Cefuroxime sodium connect cis methoxy imino group, have strengthened the stability of beta-lactam nucleus parent nucleus to enzyme greatly from three-dimensional arrangement, have enlarged antimicrobial spectrum, have strengthened anti-microbial activity; Medicine is improved the stability of enzyme, help bringing into play anti-microbial activity, prevent the appearance of pathogenic strains.Cefuroxime sodium is high to the stability of the β-Nei Xiananmei that pathogenic bacterium produce far beyond the first-generation and other second generation cephalosporins, even surpasses the cefoperazone of the third generation.Cefuroxime sodium be possess the first-generation and third generation cephalosporin advantage classic two generation cynnematin, not only gram-positive cocci there is stronger anti-microbial activity, and some gram negative bacterium also there is the excellent antibiotic activity, especially in the treatment of Gram-positive and gram negative bacterium polyinfection, the medicine of preferentially selecting for use especially.Cefuroxime sodium is wide owing to distributing in has a broad antifungal spectrum, the body, tissue concentration is high, toxicity is low, is applicable to respiratory tract infection, urinary tract infection, otorhinolaryngology infection, skin and soft tissue infection, Obstetric and Gynecologic Department infection, gonorrhoea, septicemia, meningitis and inside and outside postoperative infection.Cefuroxime sodium not only is used for anti-infective therapy, and curative effect was very obvious during anti-infective therapy and surgical prophylaxis infected after surgery.Cefuroxime sodium is not in vivo by liver metabolism, so to the liver nontoxicity; From urine, drain through kidney with original shape, so,, the newborn infant is had good pharmacokinetics and security so its medication is as safe as a house to the almost non-toxic side effect of kidney.The synthetic of Cefuroxime sodium is starting raw material with Glaxo) (Wilson E M., Chemistry and Industry, 1984,217) or with 7-ACA (7-amino-cephalosporanic acid).
With the Glaxo) is that the starting raw material route is as follows:
This route shortcoming is that the Glaxo) unit consumption is too high, and reactions steps is many, and the cost height does not have producer to adopt this route now.
Producing Cefuroxime sodium now is starting raw material with 7-ACA mainly, and two class synthetic methods are arranged.The first kind is earlier with [cis]-2-[2-furyl]-the 2-[methoxyimino] Acetyl Chloride 98Min. reacts with 7 bit aminos of 7-ACA; use 3 ester groups of the cephalosporium acetylesterase selective hydrolysis 7-ACA of scarlet yeast (Rhodotorula rubra) fermentation generation again; make 3-deammoniation formyl radical cefuroxime acid (3-decarbamoyl cefuroxime) and be called for short DCCF; 3 hydroxyls transforming DCCF again transform carboxamide oxygen methyl as and obtain cefuroxime acid (Chen Fener etc.; organic drug synthesis method [M]; Beijing: Chinese Medicine science and technology press; 1999; 600-604); the cephalosporium acetylesterase that scarlet yeast (Rhodotorula rubra) fermentation at present produces costs an arm and a leg and does not domesticly have an industrialization supplier, has limited the application of the first kind.Its synthetic route is as follows:
Second class methods are with 3 the ester group (Smiths of 7-ACA by the cephalosporium acetylesterase selective hydrolysis 7-ACA of scarlet yeast (Rhodotorula rubra) fermentation generation; Alan; Ulverston; et al; Preparation ofcephalosporin compounds.US:3912589; 1975) make key intermediate 3-deacetylation-7-amino-Cephalosporanic acid (3-deaacetyl-7-amino-cephalosporin acid; 7-DACA), obtain cefuroxime acid through two approach then.Article one, approach is introduced [cis]-2-[2-furyl at 7 bit aminos after earlier transforming 3 methylols of 7-DACA as carboxamide oxygen methyl again]-the 2-[methoxyimino] acetate obtains cefuroxime acid, this approach shortcoming be transform 7-DACA with isocyanic ester 3 methylols simultaneously with the 7 bit aminos reaction of 7-DACA, cause part 7 bit aminos of 7-DACA can't be again and [cis]-2-[2-furyl]-the 2-[methoxyimino] excess acetyl chloride, impurity is more in the product, purity is low, be difficult for reaching medicinal requirements, generally do not adopt this route (Cook M C now, Gregory G l, BradshawJ, etal.Cephalosporin antibiotics[P] .GB 1,1453.049 (1973-08-21)).The second approach is that 7 bit aminos of 7-DACA are introduced side chain [cis]-2-[2-furyl]-the 2-[methoxyimino] acetate obtains 3-deammoniation formyl radical cefuroxime acid (3-decarbamoyl cefuroxime; be called for short DCCF), transform 3 methylols of DCCF as carboxamide oxygen methyl again and make cefuroxime acid.The common drawback of second class methods is that 7-ACA passes through the cephalosporium acetylesterase selective hydrolysis that scarlet yeast (Rhodotorula rubra) fermentation produces and makes 7-DACA, and cephalosporium acetylesterase costs an arm and a leg; Long reaction time needs 25 ℃ of reactions 32 hours, 7-ACA, 7-DACA for a long time in the aqueous solution in its molecular structure the easy hydrolysis of tetra-atomic ring lactam bond cause the tetra-atomic ring open loop and easier hydrolysis under 25 ℃, the enzymatic hydrolysis concentration of substrate is low to cause aftertreatment very difficult; Product 7-DACA crystallization carefully causes filtering and dry difficulty is difficult to suitability for industrialized production, also having a shortcoming is that the 7-DACA precipitated crystal is need be adjusted to acidity the time, the carboxyl of 7-DACA forms the lactone of following structure easily with 3 methylol generation esterification, this lactone can't separate near aftertreatment with 7-DACA character very much, causes finished product purity low.
Technology contents
Technical problem to be solved by this invention is to overcome prior art above shortcomings part, 3 ester groups that adopt the hydrolysis of mineral alkali cryogenic selective to slough 7-ACA prepare 7-DACA, freeze for preventing reaction system, add the part organic solvent, for the lactone of avoiding forming 7-DACA directly participates in next step reaction with 7-DACA solution form; Carry out C with chloride method
7-amino preparation the DCCF (3-deammoniation formyl radical-cefuroxime acid) that transforms; transform 3 methylols of DCCF as carboxamide oxygen methyl again and make cefuroxime acid; directly change sodium and obtain the Cefuroxime sodium crude product, by the refining Cefuroxime sodium finished product that obtains of dilution crystallization method.The mineral alkali of preparation 7-DACA step comprises sodium hydroxide, lithium hydroxide, potassium hydroxide or their mixture, preferred sodium hydroxide.The organic solvent that preparation 7-DACA step is added comprises single solvent such as methyl alcohol, ethanol, Virahol, acetone, tetrahydrofuran (THF), also can be the mixed solvent of multiple organic solvent such as methyl alcohol and ethanol composition, particular methanol.C
7-amino transformation catalyzer is DMAP.That whole technology reaches is easy and simple to handle, three waste discharge is few, raw and auxiliary material all domesticizes, purpose with low cost.
For achieving the above object, the technical solution used in the present invention is such: i.e. a kind of synthetic method of Cefuroxime sodium, method comprises the following steps:
(1) 7-amino-cephalosporanic acid (7-ACA) obtains 3-deacetylation-7-amino-Cephalosporanic acid (7-DACA) with the alkali aqueous solution selective hydrolysis;
(2) with 4-Dimethylamino pyridine catalysis 3-deacetylation-7-amino-Cephalosporanic acid and [cis]-2-[2-furyl]-the 2-[methoxyimino] the Acetyl Chloride 98Min. condensation obtains 3-deammoniation formyl radical cefuroxime acid;
(3) methylol with 3 of Sulfuryl chloride isocyanate (CSI) transformation 3-deammoniation formyl radical cefuroxime acids obtains cefuroxime acid, directly handles obtaining the Cefuroxime sodium crude product with Sodium isooctanoate;
(4) the Cefuroxime sodium crude product is by the refining Cefuroxime sodium finished product that obtains of dilution crystallization method.
Synthetic route is as follows:
In the above-mentioned steps (1): 7-ACA (formula VI) is suspended in methanol aqueous solution, stir cooling, drip alkali aqueous solution, accurately control 11.5-12.5, keep-13 ℃ to-18 ℃, regulate pH value after the HPLC on-line monitoring is reached home and obtain 7-DACA solution (V) to 7.0 ∽ 8.5.
In above-mentioned steps (2), add catalyzer 4-Dimethylamino pyridine to 7-DACA solution (V) solution, ratio by 7-ACA and DMAP weight is 100: 3～10, dropping is 1: a 1.25～1.3[cis by the ratio with 7-ACA weight]-the 2-[2-furyl]-the 2-[methoxyimino] dichloromethane solution of Acetyl Chloride 98Min. (IV), drip the sig water equilibrated ph value simultaneously.After reaching home, the HPLC on-line monitoring regulates pH value to 2～3 acidizing crystals with weak acid, suction filtration, and vacuum-drying gets DCCF (III)
In above-mentioned steps 3,3-deammoniation formyl radical-cefuroxime acid (DCCF) that step (2) is obtained (III) is dissolved in anhydrous acetonitrile, stirs cooling, drips chlorosulfonic acid isocyanate, insulation reaction 1～1.5 hour, and TLC detects feedstock conversion and finishes.Drip the Sodium isooctanoate acetone soln and be cooled to separate out white crystal, suction filtration gets Cefuroxime sodium crude product (I).
At last, the Cefuroxime sodium crude product is obtained the Cefuroxime sodium finished product by dilution crystallization.
Method of the present invention has following characteristics:
1, in the step 1: the 7-ACA hydrolysis is with sodium hydroxide or lithium hydroxide or potassium hydroxide purification of aqueous solutions, and transformation efficiency is all greater than 90%, and is with low cost, and it is convenient to handle.
2, in the step 2: 7-DACA solution and [cis]-2-[2-furyl]-the 2-[methoxyimino] catalyzer of Acetyl Chloride 98Min. is 4-Dimethylamino pyridine (DMAP), the reaction times shortens, and has accelerated speed of response.
3, in the step 3: directly obtain the Cefuroxime sodium crude product by the chlorosulfonic acid isocyanate esterification, reduced the operation steps of cefuroxime acid.
4, the refining employing dilution crystallization method of the 3rd step Cefuroxime sodium in the step 4.
Description of drawings
Accompanying drawing 1 is a product content analysis report book.
The specific embodiment mode
The invention will be further described below by embodiment.The preparation method who should be noted that the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention.
Under design prerequisite of the present invention to of the present invention in following examples, the per-cent that relates to is weight percent, all temperature are centigradetemperature and have used following abbreviation:
The 7-ACA:7-amino-cephalo-alkanoic acid
7-DACA:3-deacetylation-7-amino-Cephalosporanic acid
DCCF:3-deammoniation formyl radical cefuroxime acid
CSI: Sulfuryl chloride isocyanate
The DMAP:4-Dimethylamino pyridine
HPLC: high performance liquid chromatography.
The preparation of embodiment 1 7-DACA implements 1
Add methyl alcohol 600ml, purified water 600ml, 7-ACA100g in three mouthfuls of reaction flasks, stirring cools to-15 ℃, drips 15% sodium hydroxide purification of aqueous solutions, and controlled temperature is 11.5-12.5 for-13 ℃ to-18 ℃ pH values, HPLC detects 7-ACA peak completely dissolve reaction end, about 1 hour of time.The hydrochloric acid that drips 2mol/L is regulated PH to 7.0 ∽ 8.5, and it is stand-by to obtain solution low temperature, 7-DACA Solution H PLC normalization method content 99.5%, transformation efficiency 93%.
The preparation of embodiment 2 7-DACA implements 2
Add methyl alcohol 600ml, purified water 600ml, 7-ACA100g in three mouthfuls of reaction flasks, stirring cools to-15 ℃, drips 16% lithium hydroxide purification of aqueous solutions, and controlled temperature is 11.5-12.5 for-13 ℃ to-18 ℃ pH values, HPLC detects 7-ACA peak completely dissolve reaction end, about 1 hour of time.The hydrochloric acid that drips 2mol/L is regulated PH to 7.0 ∽ 8.5, and it is stand-by to obtain solution low temperature, 7-DACA Solution H PLC normalization method content 99.5%, transformation efficiency 92%.
The preparation of embodiment 3 7-DACA implements 3
Add methyl alcohol 600ml, purified water 600ml, 7-ACA100g in three mouthfuls of reaction flasks, stirring cools to-15 ℃, drips 14% potassium hydroxide purification of aqueous solutions, and controlled temperature is 11.5-12.5 for-13 ℃ to-18 ℃ pH values, HPLC detects 7-ACA peak completely dissolve reaction end, about 1 hour of time.The hydrochloric acid that drips 2mol/L is regulated PH to 7.0 ∽ 8.5, and it is stand-by to obtain solution low temperature, 7-DACA Solution H PLC normalization method content 99.5%, transformation efficiency 90%.
The preparation of embodiment 4 DCCF
Temperature control-10 ℃, 4-Dimethylamino pyridine (DMAP) 3g will be added in the 7-DACA solution of above-mentioned enforcement 1～3 one of them acquisition, with [cis]-2-[2-furyl]-the 2-[methoxyimino] the methylene dichloride 120ml drips of solution of Acetyl Chloride 98Min. 125g is added in the 7-DACA water liquid, and 10% sodium hydroxide solution that drips the purified water preparation simultaneously keeps PH8.Finish, it is reaction end that HPLC detects 7-DACA revolution mark＜1%, tells upper aqueous layer, adds gac 5g and stirs the half an hour of decolouring.Filter, washing cools to 5 ℃, and the hydrochloric acid that drips 4mol/L is to PH2, and insulated and stirred 2 hours is filtered, and the dry DCCF115g of getting of final vacuum is drained in the cryogenic purincation water washing, and HPLC normalization method content 99.0% is about 85% from the 7-ACA calculated yield.
The preparation of embodiment 5 Cefuroxime sodiums
Be dissolved in anhydrous acetonitrile 250ml with implementing 4 DCCF20g that obtain, stir and cool to 5 ℃, drip chlorosulfonic acid isocyanate 7ml, insulation reaction 1 hour, TLC detects feedstock conversion and finishes.The Sodium isooctanoate acetone soln of dropping 15% is cooled to-5 ℃ to PH6.7, separates out white crystal, and suction filtration gets Cefuroxime sodium crude product 21g, HPLC normalization method content 98.0%, yield 90%.
Making with extra care of embodiment 6 Cefuroxime sodiums
Be dissolved in the 100ml purified water with implementing the 5 Cefuroxime sodium crude product 20g that obtain, controlling 25 ℃ adds gac 1g after treating to dissolve fully and keeps 25 ℃ to stir 30 minutes decolorization filterings, wash the carbon slag with 100ml acetone, merging filtrate, be cooled to 5 ℃ of about 1h and drip acetone 2000ml, keeping 5 ℃ stirred at a slow speed 30 minutes, static growing the grain leached crystal in 30 minutes, vacuum-drying is to constant weight below 40 ℃, get Cefuroxime sodium 17g, yield 85%, product is according to " Chinese pharmacopoeia 2005 editions is examined content with the HPLC external standard method and reached (according to Cefuroxime sodium calculating) (referring to accompanying drawing 1) more than 99.5%, and quality product meets " Chinese pharmacopoeia 2005 editions.
Claims (3)
1, a kind of synthetic method of Cefuroxime sodium is characterized in that this method comprises the following steps: that synthetic route is as follows:
Step (1): (formula VI) is suspended in the methanol aqueous solution with the starting raw material 7-amino-cephalosporanic acid, stir cooling, drip alkali aqueous solution, accurately control 11.5-12.5, keep-13 ℃ to-18 ℃, regulate pH value after the HPLC on-line monitoring is reached home and obtain 3-deacetylation-7-amino-Cephalosporanic acid solution (formula V) to 7.0 ∽ 8.5;
Step (2): add catalyzer 4-Dimethylamino pyridine to 3-deacetylation-7-amino-Cephalosporanic acid solution (formula V) solution, ratio by 3-deacetylation-7-amino-Cephalosporanic acid and 4-Dimethylamino pyridine weight is 100: 3～10, dropping is 1: a 1.25～1.3[cis by the ratio with 7-amino-cephalosporanic acid weight]-the 2-[2-furyl]-the 2-[methoxyimino] dichloromethane solution of Acetyl Chloride 98Min. (formula IV), drip the sig water equilibrated ph value simultaneously, after reaching home, the HPLC on-line monitoring regulates pH value to 2～3 acidizing crystals with weak acid, suction filtration, vacuum-drying get 3-deammoniation formyl radical cefuroxime acid (formula III);
Step (3): 3-deammoniation formyl radical-cefuroxime acid (formula III) that step (2) is obtained is dissolved in anhydrous acetonitrile, stir cooling, drip chlorosulfonic acid isocyanate, insulation reaction 1～1.5 hour, TLC detects feedstock conversion and finishes, drip the Sodium isooctanoate acetone soln and be cooled to separate out white crystal, suction filtration gets Cefuroxime sodium crude product (formula I);
Step (4): the Cefuroxime sodium crude product is obtained the Cefuroxime sodium finished product by dilution crystallization.
2, the synthetic method of a kind of Cefuroxime sodium according to claim 1 is characterized in that the alkali aqueous solution of using is sodium hydroxide or lithium hydroxide or potassium hydroxide or their mixture in step (1).
3, the synthetic method of a kind of Cefuroxime sodium according to claim 1 is characterized in that 3-deacetylation-7-amino-Cephalosporanic acid and [cis]-2-[2-furyl in step (2)]-the 2-[methoxyimino] catalyzer of Acetyl Chloride 98Min. condensation is the 4-Dimethylamino pyridine.
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