CN104130273A - Method for synthesizing ceftriaxone sodium - Google Patents
Method for synthesizing ceftriaxone sodium Download PDFInfo
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- CN104130273A CN104130273A CN201410406285.9A CN201410406285A CN104130273A CN 104130273 A CN104130273 A CN 104130273A CN 201410406285 A CN201410406285 A CN 201410406285A CN 104130273 A CN104130273 A CN 104130273A
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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
Abstract
The invention discloses a method for synthesizing ceftriaxone sodium. The method comprises the steps of firstly carrying out condensation on 7-ACA and triazine ring by taking dimethyl carbonate and organic acid as a mixed solvent and taking boron trifluoride dimethyl carbonate as a catalyst, so as to produce 7-ACT, then, enabling 7-ACT and AE (Active Ester) to react by taking tetramethyl guanidine as a cosolvent, so as to produce ceftriaxone, and finally, adding sodium acetate, thereby synthesizing the sodium salt. The method has the advantages that the operating method is simple, the conditions are mild, the raw materials are easily available, the pollution is little, the cost is very low, the purity of the finally obtained ceftriaxone sodium product is over 99.6%, and the molar yield is over 94%.
Description
Technical field
The present invention relates to medical technical field, be specifically related to the synthetic method of ceftriaxone sodium.
Background technology
Ceftriaxone sodium; claim again rocephin; that Rochen company of Switzerland is in the Third generation Cephalosporins microbiotic of the eighties of last century popularization eighties; English name is Ceftriaxone Sodium; chemical name is (6R; 7R)-7-[[(2-amino-4-thiazolyl) (methoxyimino) ethanoyl] amino]-8-oxo-3-[[(1; 2; 5; 6-tetrahydrochysene-2-methyl-5; 6-dioxo-1,2,4-triazine-3-yl) sulfo-] methyl]-three times of semihydrates of 5-thia-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid disodium salt.Chemical structural formula is as follows:
Ceftriaxone sodium has powerful anti-microbial activity for gram positive organism and negative bacterium, and antimicrobial spectrum comprises Pseudomonas aeruginosa, intestinal bacteria, pneumobacillus, hemophilus influenzae, aerogenesis enterobacteria, proteus, Diplococcus and golden Portugal bacterium etc.Clinical meningitis, pneumonia, skin soft-tissue infection, peritonitis, urinary system infection, gonorrhoea, liver and gall infection, the surgical wound that sensitive organism infects, septicemia and the genital infection etc. of being mainly used in.As the First Line medicine for the treatment of gonorrhoea.
Mostly the method for now synthetic Qusong sodium is with acetonitrile as solvent, boron trifluoride acetonitrile is as catalyzer, react and first generate 7-ACT with triazine ring and 7-ACA, react with MEAM and generate ceftriaxone with 7-ACT again, then add one or more in sodium acetate or Sodium isooctanoate or sodium carbonate to become sodium salt crude product, then obtain the finished product through an one-step refining.
Chinese patent CN 103539803A synthesizes 7-ACT as solvent boron trifluoride methylcarbonate as catalyzer with methylcarbonate, but its reaction times is 50min left and right, time is longer, because its comparatively high temps reaction at 30 DEG C is all greatly affected the purity of 7-ACT and yield.
Chinese patent CN 100335485C has introduced and has a kind ofly made 7-ACT react the method that generates ceftriaxone with MEAM as solvent triethylamine as solubility promoter with methylene dichloride and ethanol, but the triethylamine toxicity of using in this method is large and make to operate cumbersome and be difficult to control with nitrogen protection.
To sum up, urgently research and develop a kind of improved ceftriaxone sodium synthesis technique.
Summary of the invention
The defect existing for prior art, the invention provides a kind of synthetic method of ceftriaxone sodium, adopt the mixed system of methylcarbonate and methylsulfonic acid as solvent, temperature of reaction is reduced, reaction times shortens, and the yield of 7-ACT and purity are all significantly improved; Use the lower tetramethyl guanidine of toxicity as solubility promoter, under cold condition, reaction greatly reduces side reaction, simple to operate without nitrogen protection, has improved yield and the quality of ceftriaxone sodium.
The synthetic method that the present invention relates to a kind of ceftriaxone sodium, is achieved through the following technical solutions:
A synthetic method for ceftriaxone sodium, comprises following processing step:
(1) prepare 7-ACT
In dry four-necked bottle, add methylcarbonate, boron trifluoride methylcarbonate, organic acid; Rapid stirring is also cooled to 10~12 DEG C, adds triazine ring, 7-ACA, keeps 10~12 DEG C of approximately 20~30min of reaction; Sampling detects when 7-ACA is residual is less than 1% and finishes to react with HPLC (high performance liquid chromatography); After reaction finishes, add a certain amount of cold water, EDTA-2Na, V-Brite B to keep temperature below 13 DEG C, dripping weak ammonia adjusting pH is 2.3~2.6, separates out white solid; Drip and finish, 5~10 DEG C of growing the grain 1h, filter, and use respectively a certain amount of purified water washing leaching cake twice, filter; Use a certain amount of washing with alcohol filter cake once again, filter, vacuum-drying obtains product.
(2) prepare ceftriaxone sodium
Above-mentioned gained solid is put in the binary solvent of methylene dichloride and ethanol composition, be cooled to below-10 DEG C, under agitation condition, drip tetramethyl guanidine, keep temperature-5~-10 DEG C, then add MEAM-5~-10 DEG C reaction 4h, after reaction finishes, be warming up to 10~15 DEG C and add a certain amount of purified water, stratification after stirring, discard organic phase, water adds sodium salt, stirring drips acetone after sodium salt is dissolved, after having crystal to separate out, stop dripping acetone, slowly stir growing the grain 1h, continue to drip acetone until no longer include crystal and separate out and stop dripping acetone, growing the grain 2h.Filter, with a certain amount of washing with acetone filter cake, filter final vacuum dry, obtain product.
Described organic acid is methylsulfonic acid or glacial acetic acid.
Described sodium salt is sodium acetate.
Described methylcarbonate and organic acid mol ratio are 5.32~63.9:1.
The mol ratio of described 7-ACT and tetramethyl guanidine is 1:2.42~3.02.
Concrete synthetic route is as follows:
Synthetic 7-ACT route:
Synthetic ceftriaxone route:
Become sodium salt route:
The chemical name of correlated response raw material is as follows:
Triazine ring: 2,5-dihydro-6-hydroxyl-3-sulfydryl-2-methyl isophthalic acid, 2,4-triazine-5-ketone
The amino cephalo enzyme of 7-ACA:7-alkanoic acid
The amino rocephin of 7-ACT:7-
MEAM: 2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetic acid sulfo-benzothiazole ester
EDTA-2Na: disodium ethylene diamine tetraacetate
Compared with prior art, the present invention has the following advantages:
This invention is with not using the acetonitrile of high poison as solvent, the methylcarbonate of using is that green and environment-friendly solvent and cost are 1/3rd of acetonitrile, environmentally friendly and greatly reduce cost, and greatly accelerated speed of response because methylcarbonate and organic acid mix to use, make reaction can be at relative low temperature (10-12 DEG C) thus under condition, make by product significantly reduce the yield and the quality that have improved product; The present invention makes the reaction times shorten to 2.5~4h with tetramethyl guanidine as solubility promoter; Reaction just can be carried out without nitrogen protection, has reduced the loaded down with trivial details degree of operation, has increased industrial feasibility; The Qusong sodium product purity finally obtaining is more than 99.7%, and molar yield is more than 92%, and yield and the quality of product increase.
Embodiment
Further describe the present invention by following examples, but should notice that scope of the present invention is not subject to any restriction of these embodiment.
Embodiment 1 prepares 7-ACT
In dry four-necked bottle, add methylcarbonate 120g, boron trifluoride methylcarbonate 56g, methylsulfonic acid 8g, rapid stirring is cooled to 10 DEG C, add triazine ring 15g, 7-ACA25g, keep 10~12 DEG C of about 23min of reaction, sampling is less than 1% reaction and finishes with HPLC (high performance liquid chromatography) detection 7-ACA is residual.In four-necked bottle, add cold water 240g, solution clarification, adds EDTA-2Na0.25g, V-Brite B 1.0g to keep temperature below 13 DEG C, drip weak ammonia (1:1) and regulate pH=2.3~2.6, separate out white solid, drip and finish 5~10 DEG C of growing the grain 1h, filter, use respectively 120g water washing filter cake twice, filter, use 50g washing with alcohol filter cake once, filter, 45 DEG C of vacuum-drying 8h obtain solid 32.5g, molar yield 95.1%, purity 99.40%.
Embodiment 2 prepares 7-ACT
In dry four-necked bottle, add methylcarbonate 120g, boron trifluoride methylcarbonate 56g, methylsulfonic acid 7g, rapid stirring is cooled to 10 DEG C, add triazine ring 15g, 7-ACA25g, keep 10~12 DEG C of about 23min of reaction, sampling is less than 1% reaction and finishes with HPLC (high performance liquid chromatography) detection 7-ACA is residual.In four-necked bottle, add cold water 240g, solution clarification, adds EDTA-2Na0.25g, V-Brite B 1.0g to keep temperature below 13 DEG C, drip weak ammonia (1:1) and regulate pH=2.3~2.6, separate out white solid, drip and finish 5~10 DEG C of growing the grain 1h, filter, use respectively 120g water washing filter cake twice, filter, use 50g washing with alcohol filter cake once, filter, 45 DEG C of vacuum-drying 8h obtain solid 32.1g, molar yield 93.9%, purity 99.35%.
Embodiment 3 prepares 7-ACT
In dry four-necked bottle, add methylcarbonate 120g, boron trifluoride methylcarbonate 56g, methylsulfonic acid 6g, rapid stirring is cooled to 11 DEG C, add triazine ring 15g, 7-ACA25g, keep 10~12 DEG C of about 25min of reaction, sampling is less than 1% reaction and finishes with HPLC (high performance liquid chromatography) detection 7-ACA is residual.In four-necked bottle, add cold water 240g, solution clarification, adds EDTA-2Na0.25g, V-Brite B 1.0g to keep temperature below 13 DEG C, drip weak ammonia (1:1) and regulate pH=2.3~2.6, separate out white solid, drip and finish 5~10 DEG C of growing the grain 1h, filter, use respectively 120g water washing filter cake twice, filter, use 50g washing with alcohol filter cake once, filter, 45 DEG C of vacuum-drying 8h obtain solid 32.0g, molar yield 93.7%, purity 99.51%.
Embodiment 4 prepares 7-ACT
In dry four-necked bottle, add methylcarbonate 120g, boron trifluoride methylcarbonate 56g, methylsulfonic acid 5g, rapid stirring is cooled to 12 DEG C, add triazine ring 15g, 7-ACA25g, keep 10~12 DEG C of about 28min of reaction, sampling is less than 1% reaction and finishes with HPLC (high performance liquid chromatography) detection 7-ACA is residual.In four-necked bottle, add cold water 240g, solution clarification, adds EDTA-2Na0.25g, V-Brite B 1.0g to keep temperature below 13 DEG C, drip weak ammonia (1:1) and regulate pH=2.3~2.6, separate out white solid, drip and finish 5~10 DEG C of growing the grain 1h, filter, use respectively 120g water washing filter cake twice, filter, use 50g washing with alcohol filter cake once, filter, 45 DEG C of vacuum-drying 8h obtain solid 32.3g, molar yield 94.5%, purity 99.62%.
Embodiment 5 prepares 7-ACT
In dry four-necked bottle, add methylcarbonate 120g, boron trifluoride methylcarbonate 56g, methylsulfonic acid 2g, rapid stirring is cooled to 10 DEG C, add triazine ring 15g, 7-ACA25g, keep 10~12 DEG C of about 30min of reaction, sampling is less than 1% reaction and finishes with HPLC (high performance liquid chromatography) detection 7-ACA is residual.In four-necked bottle, add cold water 240g, solution clarification, adds EDTA-2Na0.25g, V-Brite B 1.0g to keep temperature below 13 DEG C, drip weak ammonia (1:1) and regulate pH=2.3~2.6, separate out white solid, drip and finish 5~10 DEG C of growing the grain 1h, filter, use respectively 120g water washing filter cake twice, filter, use 50g washing with alcohol filter cake once, filter, 45 DEG C of vacuum-drying 8h obtain solid 31.3g, molar yield 91.6%, purity 99.32%.
Embodiment 6 prepares 7-ACT
In dry four-necked bottle, add methylcarbonate 120g, boron trifluoride methylcarbonate 56g, acetic acid 5g, rapid stirring is cooled to 12 DEG C, add triazine ring 15g, 7-ACA25g, keep 10~12 DEG C of about 27min of reaction, sampling is less than 1% reaction and finishes with HPLC (high performance liquid chromatography) detection 7-ACA is residual.In four-necked bottle, add cold water 240g, solution clarification, adds EDTA-2Na0.25g, V-Brite B 1.0g to keep temperature below 13 DEG C, drip weak ammonia (1:1) and regulate pH=2.3~2.6, separate out white solid, drip and finish 5~10 DEG C of growing the grain 1h, filter, use respectively 120g water washing filter cake twice, filter, use 50g washing with alcohol filter cake once, filter, 45 DEG C of vacuum-drying 8h obtain solid 31.5g, molar yield 92.2%, purity 99.41%.
Embodiment 7 prepares 7-ACT
In dry four-necked bottle, add methylcarbonate 120g, boron trifluoride methylcarbonate 56g, acetic acid 10g, rapid stirring is cooled to 12 DEG C, add triazine ring 15g, 7-ACA25g, keep 10~12 DEG C of about 24min of reaction, sampling is less than 1% reaction and finishes with HPLC (high performance liquid chromatography) detection 7-ACA is residual.In four-necked bottle, add cold water 240g, solution clarification, adds EDTA-2Na0.25g, V-Brite B 1.0g to keep temperature below 13 DEG C, drip weak ammonia (1:1) and regulate pH=2.3~2.6, separate out white solid, drip and finish 5~10 DEG C of growing the grain 1h, filter, use respectively 120g water washing filter cake twice, filter, use 50g washing with alcohol filter cake once, filter, 45 DEG C of vacuum-drying 8h obtain solid 30.8g, molar yield 92.1%, purity 99.52%.
Embodiment 8 prepares 7-ACT
In dry four-necked bottle, add methylcarbonate 120g, boron trifluoride methylcarbonate 56g, acetic acid 15g, rapid stirring is cooled to 12 DEG C, add triazine ring 15g, 7-ACA25g, keep 10~12 DEG C of about 20min of reaction, sampling is less than 1% reaction and finishes with HPLC (high performance liquid chromatography) detection 7-ACA is residual.In four-necked bottle, add cold water 240g, solution clarification, adds EDTA-2Na0.25g, V-Brite B 1.0g to keep temperature below 13 DEG C, drip weak ammonia (1:1) and regulate pH=2.3~2.6, separate out white solid, drip and finish 5~10 DEG C of growing the grain 1h, filter, use respectively 120g water washing filter cake twice, filter, use 50g washing with alcohol filter cake once, filter, 45 DEG C of vacuum-drying 8h obtain solid 32.2g, molar yield 94.2%, purity 99.50%.
Embodiment 9 prepares ceftriaxone sodium
16g7-ACT dry product is put in the binary solvent four-necked bottle that fills 90g methylene dichloride and 6g ethanol composition, be cooled to below-10 DEG C, under agitation condition, drip 12g tetramethyl guanidine, keep temperature-5~-10 DEG C, then add 17gAE active ester-5~-10 DEG C reaction 4h, after reaction finishes, be warming up to 10-15 DEG C and add 70g purified water, stir 10min, stratification discards organic phase, water joins in four-necked bottle, add 8.2g sodium acetate solid, stirring and dissolving, 17-20 DEG C slowly drips about 160ml acetone, be cooled to 15-17 DEG C of growing the grain 1h, continue to drip acetone 700ml, drip and finish, be cooled to 0-5 DEG C of growing the grain 2h, filter, with dry after 92ml washing with acetone filter cake, obtain 27.2g product, molar yield 95.5%, purity 99.82%.
Embodiment 10 prepares ceftriaxone sodium
16g7-ACT dry product is put in the binary solvent four-necked bottle that fills 90g methylene dichloride and 6g ethanol composition, be cooled to below-10 DEG C, under agitation condition, drip 13g tetramethyl guanidine, keep temperature-5~-10 DEG C, then add 17gAE active ester-5~-10 DEG C reaction 3.5h, after reaction finishes, be warming up to 10-15 DEG C and add 70g purified water, stir 10min, stratification discards organic phase, water joins in four-necked bottle, add 8.2g sodium acetate solid, stirring and dissolving, 17-20 DEG C slowly drips about 160ml acetone, be cooled to 15-17 DEG C of growing the grain 1h, continue to drip acetone 700ml, drip and finish, be cooled to 0-5 DEG C of growing the grain 2h, filter, with 45 DEG C of vacuum-drying 8h after 92ml washing with acetone filter cake, obtain product 27.0g, molar yield 94.8%, purity 99.80%.
Embodiment 11 prepares ceftriaxone sodium
16g7-ACT dry product is put in the binary solvent four-necked bottle that fills 90g methylene dichloride and 6g ethanol composition, be cooled to below-10 DEG C, under agitation condition, drip 14g tetramethyl guanidine, keep temperature-5~-10 DEG C, then add 17g MEAM-5~-10 DEG C reaction 2.5h, after reaction finishes, be warming up to 10-15 DEG C and add 70g purified water, stir 10min, stratification discards organic phase, water joins in four-necked bottle, add 8.2g sodium acetate solid, stirring and dissolving, 17-20 DEG C slowly drips about 160ml acetone, be cooled to 15-17 DEG C of growing the grain 1h, continue to drip acetone 700ml, drip and finish, be cooled to 0-5 DEG C of growing the grain 2h, filter, with 45 DEG C of vacuum-drying 8h after 92ml washing with acetone filter cake, obtain product 26.8g, molar yield 94.1%, purity 99.89%.
Embodiment 12 prepares ceftriaxone sodium
16g7-ACT dry product is put in the binary solvent four-necked bottle that fills 90g methylene dichloride and 6g ethanol composition, be cooled to below-10 DEG C, under agitation condition, drip 15g tetramethyl guanidine, keep temperature-5~-10 DEG C, then add 17g MEAM-5~-10 DEG C reaction 2.5h, after reaction finishes, be warming up to 10-15 DEG C and add 70g purified water, stir 10min, stratification discards organic phase, water joins in four-necked bottle, add 8.2g sodium acetate solid, stirring and dissolving, 17-20 DEG C slowly drips about 160ml acetone, be cooled to 15-17 DEG C of growing the grain 1h, continue to drip acetone 700ml, drip and finish, be cooled to 0-5 DEG C of growing the grain 2h, filter, with 45 DEG C of vacuum-drying 8h after 92ml washing with acetone filter cake, obtain product 27.1g, molar yield 95.15%, purity 99.85%.
Embodiment 13 prepares the screening of reaction solvent in 7-ACT
Use respectively methylcarbonate, methylcarbonate and methylsulfonic acid, methylcarbonate and glacial acetic acid to prepare 7-ACT as reaction solvent, screen, the results are shown in Table 1.
Table 1 is prepared reaction solvent the selection result in 7-ACT
Triazine ring is S with reacting of 7-ACA
n1 reaction, owing to adding methylsulfonic acid or glacial acetic acid to increase the acidity of solvent in reaction process, increase the proton in solvent, proton can be better with react in the negative ion that particularly formed by oxygen and nitrogen of the negative ion that produces pass through hydrogen bond solvation, make like this negative charge disperse, make negative ion stable, be therefore conducive to dissociation reaction, be conducive to S
n1 reaction is carried out.Therefore, can make reaction system more even, accelerate reaction process, improve speed of reaction.
Table 1 result shows, methylcarbonate and organic acid mix to use has accelerated speed of response greatly, and speed of response improves than the speed of reaction that uses separately methylcarbonate to do solvent; Product yield and quality are also improved simultaneously.
Embodiment 14 prepares the screening of solubility promoter in ceftriaxone sodium
Table 2 is prepared solubility promoter the selection result in ceftriaxone sodium
Solubility promoter | Temperature of reaction | Reaction times | Product yield | Product purity | Look level |
Tetramethyl guanidine | -5~-10℃ | React 4 hours | 95.5% | 99.82% | 2# |
Tetramethyl guanidine | -5~-10℃ | React 3.5 hours | 94.8% | 99.80% | 2# |
Tetramethyl guanidine | -5~-10℃ | React 2.5 hours | 94.1% | 99.89% | 2# |
Tetramethyl guanidine | -5~-10℃ | React 2.5 hours | 95.15% | 99.85% | 2# |
Triethylamine | -5~-10℃ | React 5 hours | 92.3% | 99.22% | 4# |
Triethylamine | -5~-10℃ | React 4.5 hours | 93.1% | 99.34% | 4# |
Tetramethyl guanidine can make well reaction mass dissolve in reaction process, and the acidic substance that produce in can combined reaction process, and reaction is carried out to positive reaction direction.Therefore, under lower condition, complete reaction, greatly reduce the generation of by product, both can Reaction time shorten, improve again the efficiency of reaction, improve the quality of products simultaneously.
Table 2 result is presented under identical reaction conditions that tetramethyl guanidine is obvious compared with triethylamine has shortened the reaction times, so reduced the generation of by product and then the purity of ceftriaxone sodium and yield and all increase because temperature of reaction is controlled at lesser temps.
Although illustrate and described exemplary embodiments more of the present invention, but those skilled in the art should know, without departing from the principles and spirit of the present invention, can make change to these exemplary embodiments, scope of the present invention is limited by claim and equivalent thereof.
Claims (5)
1. a synthetic method for ceftriaxone sodium, described method comprises following processing step:
(1) prepare 7-ACT
In dry four-necked bottle, add methylcarbonate, boron trifluoride methylcarbonate, organic acid; Rapid stirring is also cooled to 10 ~ 12 DEG C, adds triazine ring, 7-ACA, keeps 10 ~ 12 DEG C of approximately 20 ~ 30min of reaction; Sampling HPLC(high performance liquid chromatography) detect when 7-ACA is residual is less than 1% and finish to react; After reaction finishes, add a certain amount of cold water, EDTA-2Na, V-Brite B to keep temperature below 13 DEG C, dripping weak ammonia adjusting pH is 2.3 ~ 2.6, separates out white solid; Drip and finish, 5 ~ 10 DEG C of growing the grain 1h, filter, and use respectively a certain amount of purified water washing leaching cake twice, filter; Use a certain amount of washing with alcohol filter cake once again, filter, vacuum-drying obtains product;
(2) prepare ceftriaxone sodium
Above-mentioned gained solid is put in the binary solvent of methylene dichloride and ethanol composition, be cooled to below-10 DEG C, under agitation condition, drip tetramethyl guanidine, keep temperature-5 ~-10 DEG C, then add MEAM-5 ~-10 DEG C reaction 4h, after reaction finishes, be warming up to 10 ~ 15 DEG C and add a certain amount of purified water, stratification after stirring, discard organic phase, water adds sodium salt, stirring drips acetone after sodium salt is dissolved, after having crystal to separate out, stop dripping acetone, slowly stir growing the grain 1h, continue to drip acetone until no longer include crystal and separate out and stop dripping acetone, growing the grain 2h,
Filter, with a certain amount of washing with acetone filter cake, filter final vacuum dry, obtain product.
2. the synthetic method of ceftriaxone sodium according to claim 1, described organic acid is methylsulfonic acid or glacial acetic acid.
3. the synthetic method of ceftriaxone sodium according to claim 1, described sodium salt is sodium acetate.
4. the synthetic method of ceftriaxone sodium according to claim 1, described methylcarbonate and organic acid mol ratio are 5.32 ~ 63.9:1.
5. the synthetic method of ceftriaxone sodium according to claim 1, the mol ratio of described 7-ACT and tetramethyl guanidine is 1:2.42 ~ 3.02.
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