CN105566350B - A kind of synthetic method of cefoperazone acid - Google Patents
A kind of synthetic method of cefoperazone acid Download PDFInfo
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- CN105566350B CN105566350B CN201511010943.3A CN201511010943A CN105566350B CN 105566350 B CN105566350 B CN 105566350B CN 201511010943 A CN201511010943 A CN 201511010943A CN 105566350 B CN105566350 B CN 105566350B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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Abstract
The present invention discloses a kind of synthetic method of cefoperazone acid, includes the following steps：Under boron trifluoride acetonitrile catalysis, is reacted as raw material using 7-ACA and 1- methyl -5- mercapto tetrazoles and 7-ACT is made；7-ACT is dissolved in acetonitrile and N, in the mixed liquor of O- (double) trimethyl silane yl acetamide, obtains 7-ACT aminoalkyl compound solution；HO-EPCP, organic solvent and catalyst are mixed, reaction temperature is -25~-20 DEG C, and phosphorus oxychloride is added and is reacted, and HO-EPCP residual quantity≤0.5% in reaction solution is considered as that the reaction was complete, and HO-EPCP acyl chlorides compound solution is made；By 7-ACT aminoalkyl compound solution and HO-EPCP acyl chlorides compound solution hybrid reactions, sodium bicarbonate aqueous solution is added after reaction, stratification removes layered material liquid after filtering, adds water crystallization, be filtered, washed, be drying to obtain cefoperazone acid.The method of the present invention is simple, product yield is high, intermediate is stablized.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of synthetic method of cefoperazone acid.
Background technology
Cefoperazone sodium is that Japan folic hill chemical industrial company develops the third generation cephalosporin found, has antimicrobial spectrum
Extensively, the features such as antibacterial action is strong, it is strong to beta-lactamase tolerance, there is work to gram-positive bacteria and Gram-negative bacteria
With, for treating respiratory tract infection disease, infection of biliary tract disease, gynecological infections disease, surgical infection disease etc., into vivo after through non-spy
Anisotropic esterase hydrolyzed plays a role for cefoperazone.
Cefoperazone acid (Cefoperazone), chemical name are 7- (((4- ethyl -2,3- dioxo -1- piperazinyls)
Formamido group) (4- hydroxy phenyls) acetylamino) -3- ((1- methyl-1 H- tetrazolium -5- bases) sulfidomethyl) -8- oxo -5- sulphur -1-
Azabicyclo (4.2.0) oct-2-ene -2- formic acid, is the raw material for synthesizing cefoperazone sodium, and structural formula is：
Currently, the synthetic method of cefoperazone acid mainly has chloride method, mixed anhydride method, thioester method, amino-substituent point
Cloth condensation method, that there are costs of material is high for existing synthetic method, acyl chlorides compound intermediate is unstable, product yield is low, reaction item
The defects of part harshness, poor product quality, it is unfavorable for large-scale industrial production.
Invention content
The object of the invention is intended to provide a kind of synthetic method of cefoperazone acid.
Based on object above, the present invention takes following technical scheme：
A kind of synthetic method of cefoperazone acid, includes the following steps：
（1）Under boron trifluoride acetonitrile catalysis, is reacted as raw material using 7-ACA and 1- methyl -5- mercapto tetrazoles and 7- is made
ACT；
（2）By step（1）7-ACT be dissolved in acetonitrile and N, in the mixed liquor of O- (double) trimethyl silane yl acetamide,
7-ACT aminoalkyl compound solution is obtained, the amount ratio of the acetonitrile, 7-ACT and N, O- (double) trimethyl silane yl acetamide are
70~90 ml:13~15 g:13~15 g so that amino and carboxylic group in 7-ACT are protected；
（3）HO-EPCP, organic solvent and catalyst are mixed, phosphorus oxychloride is added and is reacted, HO- in reaction solution
EPCP residual quantity≤0.5%, is considered as that the reaction was complete, and HO-EPCP acyl chlorides compound solution is made；The organic solvent is N, N- diformazans
Yl acetamide and acetonitrile, the catalyst are trim,ethylchlorosilane, and reaction temperature is -25~-20 DEG C, the N, N- dimethyl second
Amide, acetonitrile, trim,ethylchlorosilane, HO-EPCP and phosphorus oxychloride amount ratio be 45~60 ml:25~40 ml:8~10
g:15~16 g:7.5~8.5 g；
（4）By step（2）Middle 7-ACT aminoalkyls compound solution and step（3）HO-EPCP acyl chlorides compound solution mixing
Reaction, reaction temperature are -30~-25 DEG C, and sodium bicarbonate aqueous solution is added after reaction, and stratification removes layered material liquid after filtering,
Add water crystallization, is filtered, washed, is drying to obtain cefoperazone acid white crystal.
Further, step（2）The amount ratio of middle acetonitrile, 7-ACT and N, O- (double) trimethyl silane yl acetamide are 70
~90 ml:14 g:14 g.
Further, step（3）Middle n,N-dimethylacetamide, acetonitrile, trim,ethylchlorosilane, HO-EPCP and trichlorine oxygen
The amount ratio of phosphorus is 45~60 ml:25~40 ml: 8 g:15 g: 8.1 g.
Further, step（3）In HO-EPCP residual quantities in the reaction solution are detected using HPLC.
Further, step（4）Middle 7-ACT aminoalkyls compound is 1 in molar ratio with HO-EPCP acyl chlorides compound:1~2
Mixing.
Using HPLC to step（3）In HO-EPCP acyl chlorides compound solution in HO-EPCP residual quantities be detected, examine
Surveying step is：
1）0.16 g parachloroanilinum is dissolved in 25 ml acetonitriles and the mixed liquor of 5 ml n,N-dimethylacetamide, so
After 3 g steps are added（3）HO-EPCP acyl chlorides compound solution, react 20 min after, the methanol aqueous solution with a concentration of 50% is dilute
It releases to 50 ml, obtains solution to be measured；
2）Chromatographic condition：Using octadecylsilane chemically bonded silica as filler；With 0.025mol/L phosphoric acid solutions-acetonitrile
（Volume ratio is 87:13）For mobile phase；Flow velocity is 1.5 ml/min, and inspection wavelength is 278 nm.Take 20 microlitres of steps 1）It is to be measured
Solution, after organic membrane filtration, sample detection calculates HO-EPCP residual contents（Area normalization method）.
The chemical equation of the present invention is as follows：
Compared with prior art, the invention has the advantages that：
1）Preparation method of the present invention is simple, product yield is high, intermediate is stablized, in HO-EPCP acyl chloride reactions, three
Under the catalytic action of methylchlorosilane, acyl chloride reaction progress is more thorough, and not only the conversion ratio of HO-EPCP acyl chlorides compound improves
3%, and interior HO-EPCP acyl chlorides compound zero solutions for 24 hours, improve the stability of HO-EPCP acyl chlorides compounds.
2）Sodium bicarbonate aqueous solution, stratification is added in product before crystallization, and the by-product silicon ether for reacting generation obtains effectively
Separation, cefoperazone acid crystal is easy gel during solving the problems, such as later crystallization, improves the yield of cefoperazone acid,
Product purity reaches 99% or more.
Specific implementation mode
The present invention is described in further details with reference to specific embodiment.
Embodiment 1
（1）65 g boron trifluoride acetonitriles and 6.8 g 1- methyl -5- mercapto tetrazoles are mixed, 30min is stirred, are then added
Enter 14 g 7-ACA, after reacting 1h at 30 DEG C, be transferred in 100 g purified waters and hydrolyze, at 10 DEG C, weak aqua ammonia is added to there is crystalline substance
Body occurs, 30 min of growing the grain, after continuously adding weak aqua ammonia adjusting pH to 3.0, growing the grain 1h, filters, water-soluble with a concentration of 60% acetone
After liquid washing, drying is to moisture≤1% to get 16.1 g white solid 7-ACT, purity>99%, mass yield 115%；
（2）Take 14 g steps（1）7-ACT, 77 ml acetonitriles, 14 g N, O- (double) trimethyl silane yl acetamides it is mixed
It closes, in the case where temperature is 25 DEG C, stirring and dissolving obtains 7-ACT aminoalkyl compound solution, be cooled to 0 DEG C to clarifying, spare；
（3）By 15.5 g HO-EPCP, 45 ml n,N-dimethylacetamide, 25 ml acetonitriles and 8g trim,ethylchlorosilanes
It mixes, after stirring and dissolving, is cooled to -20 DEG C, 8.1 g phosphorus oxychloride, insulation reaction are then added, HPLC tracing detections react molten
Liquid, HO-EPCP residual quantities in reaction solution<0.5%, it is considered as that the reaction was complete, reaction stops molten to get HO-EPCP acyl chlorides compounds
Liquid；
（4）At -30 DEG C, by step（2）Middle 7-ACT aminoalkyls compound solution is added drop-wise to step（3）HO-EPCP acyls
Condensation reaction is carried out in chloride solution, drips off 2 h of reaction；After reaction, it is water-soluble that a concentration of 10% sodium bicarbonate of 60 ml is added
Liquid stirs 10min, and static layering removes layered material liquid after membrane filtration, at 25 DEG C, after 130 ml purified waters are added dropwise, and growing the grain
Then 330 ml purified waters are added in 60 min, be cooled to 5 DEG C, growing the grain 2h, filtering, the acetonitrile-water for being 20% with mass concentration mixes
After closing solution washing filter cake, drying is to moisture≤6% to get 24.5g white crystal cefoperazone acids, purity>99%, quality is received
175 % of rate, two step mass yields 201%.
Embodiment 2
（1）65 g boron trifluoride acetonitriles and 6.8 g 1- methyl -5- mercapto tetrazoles are mixed, 30min is stirred, are then added
Enter 14 g 7-ACA, after reacting 1h at 30 DEG C, be transferred in 100 g purified waters and hydrolyze, at 10 DEG C, weak aqua ammonia is added to there is crystalline substance
Body occurs, 30 min of growing the grain, after continuously adding weak aqua ammonia adjusting pH to 3.0, growing the grain 1h, filters, water-soluble with a concentration of 60% acetone
After liquid washing, drying is to moisture≤1% to get 7-ACT；
（2）Take 14 g steps（1）7-ACT, 90 ml acetonitriles, 14 g N, O- (double) trimethyl silane yl acetamides it is mixed
It closes, in the case where temperature is 25 DEG C, stirring and dissolving obtains 7-ACT aminoalkyl compound solution, be cooled to 0 DEG C to clarifying, spare；
（3）15 g HO-EPCP, 60 ml n,N-dimethylacetamide, 40 ml acetonitriles and 8g trim,ethylchlorosilanes are mixed
It closes, after stirring and dissolving, is cooled to -20 DEG C, 8.1 g phosphorus oxychloride, insulation reaction are then added, HPLC tracing detections react molten
Liquid, HO-EPCP residual quantities in reaction solution<0.5%, it is considered as that the reaction was complete, reaction stops molten to get HO-EPCP acyl chlorides compounds
Liquid；
（4）At -30 DEG C, by step（2）Middle 7-ACT aminoalkyls compound solution is added drop-wise to step（3）HO-EPCP acyls
Condensation reaction is carried out in chloride solution, drips off 2 h of reaction；After reaction, it is water-soluble that a concentration of 10% sodium bicarbonate of 60 ml is added
Liquid stirs 10min, and static layering removes layered material liquid after membrane filtration, at 25 DEG C, after 130 ml purified waters are added dropwise, and growing the grain
Then 330 ml purified waters are added in 60 min, be cooled to 5 DEG C, growing the grain 2h, filtering, the acetonitrile-water for being 20% with mass concentration mixes
After closing solution washing filter cake, drying is to moisture≤6% to get 24 g white crystal cefoperazone acids, purity>99%, quality is received
Rate 171%, two step mass yields 197%.
Embodiment 3
（1）65 g boron trifluoride acetonitriles and 6.8 g 1- methyl -5- mercapto tetrazoles are mixed, 30min is stirred, are then added
Enter 14 g 7-ACA, after reacting 1h at 30 DEG C, be transferred in 100 g purified waters and hydrolyze, at 10 DEG C, weak aqua ammonia is added to there is crystalline substance
Body occurs, 30 min of growing the grain, after continuously adding weak aqua ammonia adjusting pH to 3.0, growing the grain 1h, filters, water-soluble with a concentration of 60% acetone
After liquid washing, drying is to moisture≤1% to get 7-ACT；
（2）Take 13 g steps（1）7-ACT, 70 ml acetonitriles, 13 g N, O- (double) trimethyl silane yl acetamides it is mixed
It closes, in the case where temperature is 25 DEG C, stirring and dissolving obtains 7-ACT aminoalkyl compound solution, be cooled to 0 DEG C to clarifying, spare；
（3）16 g HO-EPCP, 60 ml n,N-dimethylacetamide, 40 ml acetonitriles and 10g trim,ethylchlorosilanes are mixed
It closes, after stirring and dissolving, is cooled to -25 DEG C, 7.5 g phosphorus oxychloride, insulation reaction are then added, HPLC tracing detections react molten
Liquid, HO-EPCP residual quantities in reaction solution<0.5%, it is considered as that the reaction was complete, reaction stops molten to get HO-EPCP acyl chlorides compounds
Liquid；
（4）At -25 DEG C, by step（2）Middle 7-ACT aminoalkyls compound solution is added drop-wise to step（3）HO-EPCP acyls
Condensation reaction is carried out in chloride solution, drips off 2 h of reaction；After reaction, it is water-soluble that a concentration of 10% sodium bicarbonate of 60 ml is added
Liquid stirs 10min, and static layering removes layered material liquid after membrane filtration, at 25 DEG C, after 130 ml purified waters are added dropwise, and growing the grain
Then 330 ml purified waters are added in 60 min, be cooled to 5 DEG C, growing the grain 2h, filtering, the acetonitrile-water for being 20% with mass concentration mixes
After closing solution washing filter cake, drying is to moisture≤6% to get white crystal cefoperazone acid, purity>99%.
Embodiment 4
（1）65 g boron trifluoride acetonitriles and 6.8 g 1- methyl -5- mercapto tetrazoles are mixed, 30min is stirred, are then added
Enter 14 g 7-ACA, after reacting 1h at 30 DEG C, be transferred in 100 g purified waters and hydrolyze, at 10 DEG C, weak aqua ammonia is added to there is crystalline substance
Body occurs, 30 min of growing the grain, after continuously adding weak aqua ammonia adjusting pH to 3.0, growing the grain 1h, filters, water-soluble with a concentration of 60% acetone
After liquid washing, drying is to moisture≤1% to get 7-ACT；
（2）Take 15 g steps（1）7-ACT, 90 ml acetonitriles, 15 g N, O- (double) trimethyl silane yl acetamides it is mixed
It closes, in the case where temperature is 25 DEG C, stirring and dissolving obtains 7-ACT aminoalkyl compound solution, be cooled to 0 DEG C to clarifying, spare；
（3）16 g HO-EPCP, 50 ml n,N-dimethylacetamide, 30 ml acetonitriles and 9g trim,ethylchlorosilanes are mixed
It closes, after stirring and dissolving, is cooled to -20 DEG C, 8.5 g phosphorus oxychloride, insulation reaction are then added, HPLC tracing detections react molten
Liquid, HO-EPCP residual quantities in reaction solution<0.5%, it is considered as that the reaction was complete, reaction stops molten to get HO-EPCP acyl chlorides compounds
Liquid；
（4）At -30 DEG C, by step（2）Middle 7-ACT aminoalkyls compound solution is added drop-wise to step（3）HO-EPCP acyls
Condensation reaction is carried out in chloride solution, drips off 2 h of reaction；After reaction, it is water-soluble that a concentration of 10% sodium bicarbonate of 60 ml is added
Liquid stirs 10min, and static layering removes layered material liquid after membrane filtration, at 25 DEG C, after 130 ml purified waters are added dropwise, and growing the grain
Then 330 ml purified waters are added in 60 min, be cooled to 5 DEG C, growing the grain 2h, filtering, the acetonitrile-water for being 20% with mass concentration mixes
After closing solution washing filter cake, drying is to moisture≤6% to get white crystal cefoperazone acid, purity>99%.
Claims (5)
1. a kind of synthetic method of cefoperazone acid, which is characterized in that include the following steps：
（1）Under boron trifluoride acetonitrile catalysis, is reacted as raw material using 7-ACA and 1- methyl -5- mercapto tetrazoles and 7-ACT is made；
（2）By step（1）7-ACT be dissolved in acetonitrile and N, in the mixed liquor of O- (double) trimethyl silane yl acetamide, obtain 7-
ACT aminoalkyl compound solution, the acetonitrile, 7-ACT and N, the amount ratio of O- (double) trimethyl silane yl acetamide is 70~
90 ml:13~15 g:13~15 g；
（3）HO-EPCP, organic solvent and catalyst are mixed, phosphorus oxychloride is added and is reacted, HO-EPCP in reaction solution
Residual quantity≤0.5%, is considered as that the reaction was complete, and HO-EPCP acyl chlorides compound solution is made；The organic solvent is N, N- dimethyl second
Amide and acetonitrile, catalyst are trim,ethylchlorosilane, and reaction temperature is -25~-20 DEG C, the n,N-dimethylacetamide, second
Nitrile, trim,ethylchlorosilane, HO-EPCP and phosphorus oxychloride amount ratio be 45~60 ml:25~40 ml:8~10 g:15~
16 g:7.5~8.5 g；
（4）By step（2）Middle 7-ACT aminoalkyls compound solution and step（3）The mixing of HO-EPCP acyl chlorides compound solution it is anti-
It answers, reaction temperature is -30~-25 DEG C, and sodium bicarbonate aqueous solution is added after reaction, and stratification is removed layered material liquid after filtering, added
Water crystallization is filtered, washed, is drying to obtain cefoperazone acid white crystal.
2. the synthetic method of cefoperazone acid according to claim 1, which is characterized in that step（2）Middle acetonitrile, 7-ACT
And the amount ratio of N, O- (double) trimethyl silane yl acetamide is 70~90 ml:14 g:14 g.
3. the synthetic method of cefoperazone acid according to claim 2, which is characterized in that step（3）Middle N, N- dimethyl
Acetamide, acetonitrile, trim,ethylchlorosilane, HO-EPCP and phosphorus oxychloride amount ratio be 45~60 ml:25~40 ml: 8
g:15 g: 8.1 g。
4. the synthetic method of cefoperazone acid according to claim 3, which is characterized in that step（3）In to described anti-
HO-EPCP residual quantities in solution are answered to be detected using HPLC.
5. the synthetic method of the cefoperazone acid according to claim 1,2,3 or 4, which is characterized in that step（4）Middle 7-
ACT aminoalkyls compound is 1 in molar ratio with HO-EPCP acyl chlorides compound:1~2 mixing.
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| GB1508071A (en) * | 1976-01-19 | 1978-04-19 | Toyama Chemical Co Ltd | Cephalosporins and process for producing the same |
| US20100068197A1 (en) * | 2008-07-11 | 2010-03-18 | Myriad Pharmaceuticals, Inc. | Pharmaceutical compounds as inhibitors of cell proliferation and the use thereof |
| CN102432554B (en) * | 2011-12-27 | 2014-11-05 | 山东鑫泉医药有限公司 | Method for synthesizing D(-)-alpha-(4-ethyl-2,3-dioxypiperazine-1-methanamide) hydroxyphenylacetic acid (HO-EPCP) |
| CN102532168A (en) * | 2011-12-27 | 2012-07-04 | 山东鑫泉医药有限公司 | Synthesis method of cefoperazone acid |
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