CN101747346B - Method for synthesizing ceftriaxone sodium crude salt by phase transfer catalysis method - Google Patents
Method for synthesizing ceftriaxone sodium crude salt by phase transfer catalysis method Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 36
- FDRNWTJTHBSPMW-GNXCPKRQSA-L disodium;(6r,7r)-7-[[(2e)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(2-methyl-6-oxido-5-oxo-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound [Na+].[Na+].S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)/C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C([O-])=NN1C FDRNWTJTHBSPMW-GNXCPKRQSA-L 0.000 title claims abstract description 21
- 229960000479 ceftriaxone sodium Drugs 0.000 title claims abstract description 19
- 150000003839 salts Chemical class 0.000 title claims abstract description 17
- 238000003408 phase transfer catalysis Methods 0.000 title claims description 6
- 230000002194 synthesizing effect Effects 0.000 title claims description 5
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 claims abstract description 19
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- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 8
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical group C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims abstract description 7
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- 230000006181 N-acylation Effects 0.000 claims abstract description 5
- MEMUCXUKCBNISQ-UHFFFAOYSA-N acetonitrile;trifluoroborane Chemical compound CC#N.FB(F)F MEMUCXUKCBNISQ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000005917 acylation reaction Methods 0.000 claims abstract description 5
- 239000003054 catalyst Substances 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 239000000376 reactant Substances 0.000 claims abstract description 5
- 238000007336 electrophilic substitution reaction Methods 0.000 claims abstract description 3
- 230000008569 process Effects 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- 102000000496 Carboxypeptidases A Human genes 0.000 claims description 7
- 108010080937 Carboxypeptidases A Proteins 0.000 claims description 7
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- 230000008025 crystallization Effects 0.000 claims description 4
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- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 239000005864 Sulphur Substances 0.000 claims description 3
- 229960004755 ceftriaxone Drugs 0.000 claims description 3
- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
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- 238000001308 synthesis method Methods 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 6
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- OEOIWYCWCDBOPA-UHFFFAOYSA-N 6-methyl-heptanoic acid Chemical compound CC(C)CCCCC(O)=O OEOIWYCWCDBOPA-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- -1 acyl ammonia Chemical compound 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
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- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 206010018612 Gonorrhoea Diseases 0.000 description 2
- 201000009906 Meningitis Diseases 0.000 description 2
- 101100400378 Mus musculus Marveld2 gene Proteins 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 229960005475 antiinfective agent Drugs 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 229960004261 cefotaxime Drugs 0.000 description 2
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
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- 108020004256 Beta-lactamase Proteins 0.000 description 1
- 206010061695 Biliary tract infection Diseases 0.000 description 1
- 206010051548 Burn infection Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010058674 Pelvic Infection Diseases 0.000 description 1
- 108010087702 Penicillinase Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 206010067268 Post procedural infection Diseases 0.000 description 1
- 206010037596 Pyelonephritis Diseases 0.000 description 1
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- 206010040047 Sepsis Diseases 0.000 description 1
- 206010048038 Wound infection Diseases 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
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- 230000003301 hydrolyzing effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Cephalosporin Compounds (AREA)
Abstract
The invention relates to a synthesis method of ceftriaxone sodium crude salt. (1) Taking 7-aminocephalosporanic acid (7-ACA) and triazine ring as raw materials, adopting boron trifluoride acetonitrile as a catalyst to carry out electrophilic substitution, and finally preparing 7-ACT by an enzymolysis method at a proper pH value. (2) Adding a phase transfer catalyst into the organic phase for N-acylation reaction of the 7-ACT and AE-active ester, and salifying and crystallizing to obtain the crude ceftriaxone sodium salt. The invention prepares the 7-ACT by an enzymolysis method, avoids side reaction, improves the yield and improves the product purity. The reaction is carried out in the organic phase by the phase transfer catalyst, and the product is transferred to the water phase, thereby avoiding the continuous contact with the reactant, reducing the generation of high molecular weight impurities and finally obtaining the ceftriaxone sodium crude salt with high purity and high yield.
Description
Technical field
The present invention is a kind of process method of phase transfer catalysis process synthesizing coarse salt of ceftriaxone sodium, belongs to contain the antibiotic preparation method of cynnematin heterogeneous ring compound.
Background technology
Ceftriaxone sodium is semisynthetic third generation cephalosporin; It has germicidal action to many gram-positive microorganisms, Gram-negative bacteria and anerobes; And highly stable, thereby strengthened its anti-microbial effect to bacteriogenic most of β-Nei acyl ammonia enzyme (penicillinase and cephalosporinase).Be widely used in treatment clinically, at present as the first line medicine of treatment gonorrhoea to respiratory tract infection, urinary system infection (comprising pyelonephritis and gonorrhoea), abdominal cavity infection, pelvic infection, biliary tract infection, gastrointestinal tract infection, burn infection, wound infection, postoperative infection and average of operation periods infection mitigation, skin histology infection, bone and the infection of joint due to its responsive bacterium, septicemia, meningitis etc.Its clinical pharmacology has following characteristics, is an ideal antibacterials.
1. the germicidal action of ceftriaxone sodium mainly is to suppress the cell walls of bacterium to synthesize.Human body cell is acellular, and the wall event is not too influenced, so relative toxicity is lower.
2. has a broad antifungal spectrum is stable to β-Nei acyl ammonia enzyme.
3. long half time, single administration 24h all can bring into play anti-microbial effect.
4. hemato encephalic barrier can be passed through, meningitis can be used to treat.
5. most ofly in vivo from bile and urine, discharge with original shape, remarkable to biliary tract, urinary tract infection effect.
Ceftriaxone sodium was succeeded in developing by Switzerland Roche corporatization scholar Refiner in 1978; Nineteen eighty-two goes on the market in Switzerland first; Obtained the FDA authentication on December 21st, 1984, after its patent expiration in 1996, ceftriaxone sodium begins to grow up in China with surprising rapidity.Over nearly 5 years, it is the medicine that the anti-infective medication amount of money of whole body ranks first always, and on the prescription drugs market, the cephalo Qusong accounted for 10.2% of whole anti-infective medication market total value in 2006, occupied first of the various anti-infectives at home.According to statistics, national output was 2200 tons in 2006, increased by 31% than the last year, became the fastest-rising kind of anti-infective; 8.35 hundred million on injection powder pin.This shows that ceftriaxone has arrived a peak period in the anti-infectives market at home.It is one of the cephalosporin analog antibiotic preparation variety of 22 kinds of clinical applications of present state approval.
Present synthetic about coarse salt of ceftriaxone sodium according to the document of having reported, mainly contains following several kinds: first kind is to be that starting raw material and triazine ring are under catalyst action with 7-amino-cephalosporanic acid (7-ACA); After the hydrolysis under suitable pH value; The generation midbody (6R, 7R)-7-amino-3-{ [6-hydroxy-2-methyl-5-oxo-2,5-dihydro-1; 2,4-triazine-3-yl) sulphur] methyl }-3-cephalo-4-carboxylic acid (being called for short 7-ACT).The technical study emphasis concentrates on the condensation reaction with cefotaxime acetate (2) by 7-ACT (1).The condensation process of 7-ACT and cefotaxime acetate mainly contains chloride method, active phosphide method, active thioester method and Vilsmeir method at present.
For the compound method of having reported, there is raw materials cost high, and severe reaction conditions, long reaction time is unfavorable for the shortcoming of continuity, large-scale industrial production.The active thioester method is adopted by domestic and international most of producers, improves perfectly through studying intensively of domestic colleague, changes route and has reached higher level.The molar yield of the first step is about 80%, and the yield in second step is about 90%.The first step yield is lower, severe reaction conditions, and reaction under anhydrous system earlier, hydrolysis generates 7-ACT then, and side reaction takes place easily.In second step, product can not in time separate with reactant in the reaction, causes side reactions such as excessive condensation, causes macromolecule impurity to generate, and makes finished product defective at aspects such as specific rotation, color and lusters.The problem that needs to solve is that shortening production cycle, raising product yield and product purity reduce production costs, and improve the economic benefit of manufacturing concern.
Summary of the invention
The objective of the invention is to avoid above-mentioned weak point of the prior art, a kind of product yield is high, quality is good, the compound method of the coarse salt of ceftriaxone sodium that production cost is low and provide.
The method of phase transfer catalysis process synthesizing coarse salt of ceftriaxone sodium of the present invention comprises the steps:
(1) the synthetic 7-ACT of enzymolysis process: with 7-amino-cephalosporanic acid (7-ACA) and triazine ring is raw material, and boron trifluoride-acetonitrile catalyzer exists down, carries out electrophilic substitution reaction; Then, add Carboxypeptidase A, and regulate pH between 2.0～2.5; Be hydrolyzed and react the stable reaction end that do not become to pH, crystallization, filtration, drying make (6R, 7R)-7-amino-3-{ [6-hydroxy-2-methyl-5 oxo-2; 5-dihydro-1,2,4-triazine-3-yl) sulphur] methyl }-3-cephalo-4-carboxylic acid; Be called for short 7-ACT, wherein the Carboxypeptidase A consumption is 0.05～0.10 times of 7-ACA quality;
(2) 7-ACT and AE-active ester add phase-transfer catalyst and carry out the N-acylation reaction and make ceftriaxone acid in organic phase; Be carried out to reactant salt then and obtain coarse salt of ceftriaxone sodium; Wherein the organic phase of N-acylation reaction adopts the mixed solvent of water and methylene dichloride; Phase-transfer catalyst adopts immobilized PEG-800 (being that molecular weight is 800 immobilized polyoxyethylene glycol), and consumption is the 8-10% of 7-ACT quality.
The preferred technical qualification of the present invention are:
The mol ratio of 7-amino-cephalosporanic acid (7-ACA) and triazine ring 1: 1.2.Boron trifluoride-acetonitrile catalyst levels is 5～6 times of 7-ACA quality.The mol ratio of 7-ACT and AE-active ester is 1: 1-1: 2.
The used Carboxypeptidase A of step (1), consumption be the 7-ACA quality 0.05-0.10 doubly, control pH is at 2.0-2.5. in hydrolytic process
The process method of the synthetic ceftriaxone sodium salt of phase transfer catalysis process of the present invention is compared prior art and is had outstanding substantive distinguishing features and obvious improvement, and following beyond thought technique effect occurred:
Improved product yield and purity, the first step makes 7-ACT with enzymolysis process, and enzymolysis process has single-minded, characteristics of high efficiency simultaneously; Avoided the generation of side reaction; Yield having been improved more than 8% can reach 88%, improved product purity, is a kind of compound method of environmental protection.Step (2) resultant is transferred to water through phase-transfer catalyst, has avoided contacting with the continuation of reactant, has reduced the generation of macromolecule impurity, and crystallisation process is carried out at aqueous phase, finally obtains the coarse salt of ceftriaxone sodium of high purity, high yield.Add phase-transfer catalyst and make reaction conversion ratio improve 8%, product yield is improved more than 5%, can reach more than 95%.
(3) immobilized PEG-800 is the three-phase polymer catalyst that development in recent years is got up, and has cleaning activity, is prone to reclaim, repeat advantages such as performance is good.
Embodiment
The present invention below will combine embodiment to make further detailed description:
Comparative Examples:
1,7-ACT's is synthetic
In there-necked flask, add acetonitrile 50g, 7-ACA 20g (73.5mmol), triazine ring 20.2g (127mmol) with minor amounts of acetonitrile washing bottle wall, is cooled to below 10 ℃ under the stirring and adds BF
3-acetonitrile solution [w (BF
3)=18%] 75mL, be warming up to 30 ℃ of reaction 30min.Add purified water 150mL in the 15min, be warming up to 10 ℃～20 ℃ reaction 2h, add ammoniacal liquor reaction solution is transferred to pH 1.6～2.0, be cooled to 10 ℃ ± 1 ℃.Filter, filter cake is with acetonitrile-water, water washing, dry must 7-ACT 22g (58.8mmol), molar yield 80% [n (72ACT)/n (7--ACA) * 100%]
2, coarse salt of ceftriaxone sodium is synthetic
In there-necked flask, add mixed solvent [V (water): V (methylene dichloride)=1: 2] 138mL, 7-ACT 22g (58.67mmol) and AE active ester 21g (59mmol) at 0 ℃～2 ℃ reaction 2h, add and react 7h again after triethylamine to reaction solution is alkalescence.Add the acetone soln 78mL that contains Sodium isooctanoate 115g (230mmol) in the 1h.Be warming up to 25 ℃～27 ℃ reaction 2.5h, add acetone 330mL, be cooled to 15 ℃ ± 1 ℃ in the 1h.Filter, filter cake is used washing with acetone, dry 35.36g (53.49mmol) product, the content molar yield 91.18% [n (1)/n (7-ACT) * 100%] of getting.
Embodiment 1
1,7-ACT's is synthetic
By the preparation process of Comparative Examples, add purified water after, add solid phase Carboxypeptidase A lg again, constantly use the ammoniacal liquor of 5% (volume(tric)fraction) to regulate pH 2.0～2.5, stablize until pH constant, the also same Comparative Examples of crystallization procedure.Get dry product 23.79g, purity (HPLC) 99.25%, molar yield 85% [n (7-ACT)/n (7-ACA) * 100%] after the oven dry.
2, coarse salt of ceftriaxone sodium is synthetic
Preparation process by Comparative Examples adds mixed solvent [V (water): V (methylene dichloride)=1: 2] 138mL, the immobilized PEG-800 of 2g in there-necked flask; 7-ACT 22g (58.67mmol); An amount of triethylamine to reaction solution is alkalescence, after the dissolving, adds AE active ester 21g (59mmol) and keeps about 5 ℃; Stirring reaction 4h adds the acetone soln 78mL that contains Sodium isooctanoate 115g (230mmol) then.With an amount of sour water extractive reaction liquid, tell water, be warming up to 25 ℃～27 ℃ reaction 2.5h, add acetone 330mL, be cooled to 15 ℃ ± 1 ℃ in the 1h.Filtration, filter cake are with washing with acetone, dry 36.45g (55.8mmol), purity 99.65% (HPLC method), the molar yield 94.00% [n (1)/n (7-ACT) * 100%] of getting.
Embodiment 2
1,7-ACT's is synthetic
By the preparation process of Comparative Examples, add purified water after, add Carboxypeptidase A 1.5g again, constantly use the ammoniacal liquor of 5% (volume(tric)fraction) to regulate pH 2.0～2.5, stablize until pH constant, the also same comparison example of crystallization procedure.Get dry product 24.64g, purity (HPLC) 99.25%, molar yield 88% [n (72ACT)/n (7--ACA) * 100%] after the oven dry.
2, coarse salt of ceftriaxone sodium is synthetic
Preparation process by Comparative Examples adds mixed solvent [V (water): V (methylene dichloride)=1: 2] 138mL, the immobilized PEG-800 of 2.2g in there-necked flask; 7-ACT 22g (58.67mmol); An amount of triethylamine to reaction solution is alkalescence, after the dissolving, adds AE active ester 21g (59mmol) and keeps about 5 ℃; Stirring reaction 4h adds the acetone soln 78mL that contains Sodium isooctanoate 115g (230mmol) then.With an amount of sour water extractive reaction liquid, tell water, be warming up to 25 ℃～27 ℃ reaction 2.5h, add acetone 330mL, be cooled to 15 ℃ ± 1 ℃ in the 1h.Filtration, filter cake are with washing with acetone, dry 36.88g (55.8mmol), purity 99.65% (HPLC method), the molar yield 95.12% [n (1)/n (7-ACT) * 100%] of getting.
Claims (1)
1. the method for a phase transfer catalysis process synthesizing coarse salt of ceftriaxone sodium is characterized in that comprising the steps:
(1) the synthetic 7-ACT of enzymolysis process: with 7-amino-cephalosporanic acid and triazine ring is raw material, and boron trifluoride-acetonitrile catalyzer exists down, carries out electrophilic substitution reaction, then; Add Carboxypeptidase A, and regulate pH between 2.0～2.5, be hydrolyzed and react the stable reaction end that do not become to pH; Crystallization, filtration, drying make (6R, 7R)-7-amino-3-{ [6-hydroxy-2-methyl-5 oxo-2,5-dihydro-1; 2,4-triazine-3-yl) sulphur] methyl }-3-cephalo-4-carboxylic acid, be called for short 7-ACT; Wherein: the mol ratio of 7-amino-cephalosporanic acid (7-ACA) and triazine ring 1: 1.2; Boron trifluoride-acetonitrile catalyst levels is 5～6 times of 7-amino-cephalosporanic acid (7-ACA) quality; The Carboxypeptidase A consumption is 0.05～0.10 times of 7-amino-cephalosporanic acid quality;
(2) 7-ACT and AE-active ester add phase-transfer catalyst and carry out the N-acylation reaction and make ceftriaxone acid and be carried out to reactant salt then and obtain coarse salt of ceftriaxone sodium in organic phase; Wherein the organic phase of N-acylation reaction adopts the mixed solvent of water and methylene dichloride; Phase-transfer catalyst adopts immobilized PEG-800, and consumption is 8～10% of a 7-ACT quality; The mol ratio of 7-ACT and AE-active ester is 1: 1～1: 2.
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|---|---|---|---|---|
| CN102559829A (en) * | 2011-12-27 | 2012-07-11 | 山东鑫泉医药有限公司 | Synthetic method of ceftriaxone sodium crude salt |
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