CN106317079B - A kind of solid-phase synthesis of Ceftriaxone Sodium - Google Patents
A kind of solid-phase synthesis of Ceftriaxone Sodium Download PDFInfo
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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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Abstract
The present invention provides a kind of solid-phase synthesis of Ceftriaxone Sodium, it is characterised in that：Raw material A is bridged on solid phase carrier, is substituted, after acylation reaction, solid phase carrier is detached from and Ceftriaxone Sodium is made；The present invention by using synthesis in solid state Ceftriaxone Sodium preparation method, the last handling process after reaction can be omitted, greatly simplify response procedures, product is reduced while post-processing stages are lost, overall yield of reaction can also be increased to 90% or more, purity is increased to 99.5% or more, improves productivity effect.
Description
Technical field
The invention belongs to chemical pharmacy fields, and in particular, to a kind of solid-phase synthesis of Ceftriaxone Sodium.
Background technology：
Ceftriaxone Sodium, entitled [6R [6 α, 7 β (Z)]] -3- [[(1,2,5,6- tetrahydrochysene -2- methyl -5, the 6- dioxies of chemistry
Generation -1,2,4- triazine -3- bases) thio] methyl] -7- [[(2- amino -4- thiazolyls] (methoxyimino) acetyl group] amino] -
8- oxos -5- thia -1- azabicyclos [4.2.0] oct-2-ene -2- carboxylic acid disodium salt three times semihydrates, structural formula are：
Ceftriaxone Sodium is the long acting antibiotic class drug in Third generation Cephalosporins, it is to many Gram-positives
Bacterium, negative bacterium and anaerobic bacteria have bactericidal effect, and highly stable to bacteriogenic most of beta-lactamases, to enhance
Its antibacterial action.Clinically it is widely used in the respiratory tract infection sensitive to this product, urinary system infection contamination (including pyelonephritis
It is scorching with leaching) meningitis, infection of burn, postoperative infection, Bones and joints, soft tissue, skin and wound infection, abdominal infection etc., in addition
Also average of operation periods infection mitigation.At present using the First Line drug as treatment gonorrhoea, and the clinical application of state approval at present
One of cephalosporin analog antibiotic preparation variety.
(CN 103539803A, CN 100335485C, CN 104130273 etc.) in the prior art, 7- amino cephalo three
Piperazine is the primary raw material for synthesizing Ceftriaxone Sodium (7-ACT), it is with Acyl activating 2- (2- amino -4- thiazolyls) -2- (methoxies
Imino group) Ceftriaxone Sodium, overall yield of reaction 60% or so are obtained at salt after phenylacetic acid compound acylation reaction.In ceftriaxone
The cost of 7-ACT accounts for 70% or more in the cost of sodium, and 7-ACT is obtained in production cost, 7-amino-cephalosporanic acid (7-ACA)
Cost accounts for 80% again, so how to improve the yield of 7-ACT, reducing his production cost becomes reduction Ceftriaxone Sodium cost
Key.
Invention content
The present invention is directed to overcome drawbacks described above, for Ceftriaxone Sodium during preparation, total recovery is relatively low, and purity is not
Good and cumbersome technical problem, provides a kind of preparation method and post-processing is convenient, easy to operate, and yield is higher, purity
The method of synthesis in solid state Ceftriaxone Sodium not less than 99.5%.
The present invention provides a kind of solid-phase synthesis of Ceftriaxone Sodium, it is characterised in that：Raw material A is bridged at solid phase to carry
It on body, is substituted, after acylation reaction, is detached from solid phase carrier and Ceftriaxone Sodium is made；
Wherein, above-mentioned raw materials A is such as lower structure compound represented：
Specific reaction equation is as follows：
Wherein,Indicate solid phase carrier.
Further, the solid-phase synthesis of a kind of Ceftriaxone Sodium provided by the invention, also has the characteristics that such：I.e.,
Above-mentioned solid phase carrier is preferably resin material, such as：Selected from sulfonic polystyrene type ion exchange resin and its derivative, polystyrene benzene
Divinyl crosslinked resin and its derivative, polyacrylamide, polyethylene glycol resinoid and its derivative, chloromethyl resin and
Its derivative, carboxy resin and its derivative, amino resins and its derivative, hydrazides type resin and its one kind in derivative or
It is a variety of.
Further, the solid-phase synthesis of a kind of Ceftriaxone Sodium provided by the invention, also has the characteristics that such：I.e.,
Specific process step is as follows：
Step 1: raw material A and solid phase carrier are in organic solvent, reacted 0.5-10 hours at a temperature of 25-180 DEG C,
Obtain bridge joint product one；
The reaction preferably carries out in the container of anti-soda acid, in order to fast implement quickly dividing for the substances such as system internal solvent
From can also be selected in the container of the similar structures such as splitter and carry out, such as：In glaze glass column etc., during reaction, such as：It will
Raw material A (i.e., 7-ACA) is reacted in organic solvent with solid phase carrier, select the suitable glass column of specification, to make raw material A and
It is immobilized to be full of glaze glass column, by detection means such as TLC, HPLC, track the surplus for raw material A of dissociating to determine reaction end,
(i.e., when the raw material A of free state completely disappears or most of disappearance, raw material A all bridges at immobilized rear), after reaction terminates
With all kinds of gases such as nitrogen, air, argon gas, stream removes solvent, immobilized with organic solvent washing, removes reaction dissolvent, reaction original
Expect residue etc., directly carries out next step reaction.
In this step, the solvent of reaction preferably is selected from one or more of in halogenated hydrocarbons, amide, sulfoxide type solvents.It washes
It washs immobilized organic solvent and preferably is selected from halogenated hydrocarbons (such as：Dichloromethane, chloroform etc.), nitrogen-containing hetero aromatic hydrocarbons (such as：Pyridine etc.) etc..
Step 2: after triazine heterocyclic compound is added, 40-80 DEG C is heated in the case of protecting gas shielded；
Triazine heterocyclic compound is generally added into reaction vessels as a solution, i.e., triazine heterocyclic compound dissolving
It is added after organic solvent, which can be selected from organic solvents, the mass percent concentrations such as halogenated hydrocarbons, alkyl nitrile and be
25-85%；The protection gas can be selected from inert gas, such as：Nitrogen, argon gas, helium.
Step 3: catalyst one is added, catalysis reaction 1-5 hours obtains bridge joint product two；
All kinds of gases such as nitrogen, air, argon gas are used in reaction after terminating, stream removes solvent, immobilized with organic solvent washing,
Reaction dissolvent, reaction raw materials residue etc. are removed, next step reaction is directly carried out.It washs immobilized organic solvent and preferably is selected from halogen
(such as hydrocarbon：Dichloromethane, chloroform etc.), nitrogen-containing hetero aromatic hydrocarbons (such as：Pyridine etc.) etc..
Step 4: be added organic solvent and organic base mixed solution, be cooled in the case of protecting gas shielded 0 DEG C with
Under；
Organic solvent is selected generally from the mixed aqueous solution of halogenated hydrocarbons and alcohols, wherein halogenated hydrocarbons：Alcohols：The volume ratio of water
It is 7:0.1-2：5-8；The dosage of organic base is generally 5-10g/150-200ml solution；The dosage of the mixed solution is generally with leaching
Do not have subject to immobilized filler, dosage is generally the solution per 25g raw materials/100-250ml.
Step 5: amidation reagent is added, at a temperature of -15 DEG C -35 DEG C, react 3-10 hours, obtains bridge joint product
Three；
All kinds of gases such as nitrogen, air, argon gas are used in reaction after terminating, stream removes solvent, immobilized with organic solvent washing,
Reaction dissolvent, reaction raw materials residue etc. are removed, next step reaction is directly carried out.It washs immobilized organic solvent and preferably is selected from halogen
(such as hydrocarbon：Dichloromethane, chloroform etc.), nitrogen-containing hetero aromatic hydrocarbons (such as：Pyridine etc.) etc..
Step 6: the mixed solution of organic solvent and acid is added, reacted 1-3 hours at a temperature of 10-35 DEG C；
The volume ratio of the organic solvent and acid is preferably 5:0.5-2；
Step 7: cooling reaction system is warming up to 10-35 to -15 DEG C hereinafter, after the reaction of catalyst two being added 1-3 hours
DEG C the reaction was continued 3-10 hours；
The catalyst two is generally strong acid catalyst, to be different from the acid that solvent in step 6 is included, the catalyst
Usage amount is catalytic amount, generally the 1-10% of reactant gross mass.
Step 8: post-treated acquisition target product.
Further, the solid-phase synthesis of a kind of Ceftriaxone Sodium provided by the invention, also has the characteristics that such：I.e.,
Above-mentioned triazine heterocyclic compound is such as lower structure compound represented：
Wherein, R1 is selected from the easy groups left away such as hydrogen, halogen, ester group, alkoxy, acid halide group, hydroxyl, ester therein
Base, alkoxy, acid halide group etc. are the compound that carbon atom number is not more than 6.
Further, the solid-phase synthesis of a kind of Ceftriaxone Sodium provided by the invention, also has the characteristics that such：I.e.,
Above-mentioned amidation reagent is such as lower structure compound represented：
Wherein, above-mentioned R2 is selected from the easy groups left away such as hydrogen, halogen, ester group, alkoxy, nitro, hydroxyl, amino,
In ester group, alkoxy etc. be not more than for carbon atom number 6 compound.
Further, the solid-phase synthesis of a kind of Ceftriaxone Sodium provided by the invention, also has the characteristics that such：I.e.,
It is organic by the solvent in air-blowing method discharge system, and by least once after the completion of the reaction of above-mentioned steps one, three and five
The mode of eluent solvent obtains bridge joint product one, bridge joint product two and bridge joint product three.
Further, the solid-phase synthesis of a kind of Ceftriaxone Sodium provided by the invention, also has the characteristics that such：I.e.,
Above-mentioned organic solvent be selected from the halogenated hydrocarbons of liquid, amide, sulfur-bearing organic solvent, alkyl nitrile, alcohols, esters, ethers, heteroaryl class,
It is one or more of in aromatic solvents；
Above-mentioned organic solvent preferably is selected from dichloromethane, chloroform, dimethylformamide, dimethyl sulfoxide (DMSO), acetonitrile, methanol, second
One kind in alcohol, propyl alcohol, pyridine, tetrahydrofuran, acetone, ether, ethyl acetate, methyl acetate, toluene, benzene, dioxane or
It is several；
Above-mentioned catalyst one is selected from organic boron series catalysts；
The one kind or several of above-mentioned catalyst one in boron trihalides, alkylboronic acids, the boric acid of aromatics, organic boric acid ester
Kind；
Organic base is selected from organic amine compound, amides compound, alkoxide, metal alkyl lithium compound, nitrogenous miscellaneous
One or more of ring derivatives；
Organic base preferably is selected from triethylamine, in tetramethylguanidine, urea, sodium methoxide, sodium ethoxide, potassium tert-butoxide, tert-butyl lithium
It is one or more of；
Above-mentioned acid and catalyst two be selected from trifluoroacetic acid, hydrofluoric acid, organic sulfonic acid, one or more of containing silica reagent.
Further, the solid-phase synthesis of a kind of Ceftriaxone Sodium provided by the invention, also has the characteristics that such：I.e.,
The acidity of above-mentioned acid is better than the acidity of above-mentioned catalyst two.
Further, the solid-phase synthesis of a kind of Ceftriaxone Sodium provided by the invention, also has the characteristics that such：I.e.,
The dosage of above-mentioned raw materials A is the 5-20% of the quality of solid phase carrier；
The molar ratio of above-mentioned triazine heterocyclic compound and raw material A is 1-5:1；
The molar ratio of above-mentioned catalyst one and raw material A is 1-3:1；
The dosage of above-mentioned organic base is the 1-20% of solvent total weight in step 4；
The dosage of above-mentioned acid is the 10-30% of total solvent volume in step 6；
The molar ratio of above-mentioned acylating reagent and raw material A is 1-5:1.
Further, the solid-phase synthesis of a kind of Ceftriaxone Sodium provided by the invention, also has the characteristics that such：I.e.,
The process of above-mentioned post-processing is：
1, it by the product of step 7, filters after removing solid insoluble, except solvent obtains solid crude product；
2, it after crude product being dissolved in organic solvent, washs and extracts through sodium-salt aqueous solution at least once and extract liquor and include
There is the solution layer of product；
The organic solvent and extract liquor preferably are selected from the solvent of halogenated hydrocarbons, aromatics, ethers and esters.
The sodium salt preferably is selected from sodium bicarbonate salt, sodium chloride, sodium carbonate salt etc..Such sodium salt makes after being typically dissolved in aqueous solution
With a concentration of 25%-85% etc..
3, after crossing acid column at least once, eluent is collected；
The inner stuffing of acid column can be silica gel, seaweed sodium, activated alumina, acid ion resin etc..
4, the crystal of target product is obtained by being added into eluent after polarity poor solvent.
Poor solvent can be selected from ketone, ethers and alcohols etc..
The function and effect of the present invention：
The present invention can omit the last handling process after reaction by using the preparation method of synthesis in solid state Ceftriaxone Sodium,
Response procedures are greatly simplified, reduce product while post-processing stages are lost, moreover it is possible to which overall yield of reaction is increased to 90%
More than, purity is increased to 99.5% or more, improves productivity effect.
In addition, in the building-up process of the present invention, pass through the items such as solvent, reaction ratio, reaction temperature to reaction system
The adjustment of part realizes the effect of high yield and high-purity.
Specific implementation mode
Embodiment one：The bridging of 7-ACA and solid phase carrier
In glaze glass column, 25g 7-ACA are reacted with 100g chloromethyl resins in 100ml DMF, TLC is detected to nothing
Raw material remains, it is made fully with solid phase carrier bridging, to use N after reaction2(gases such as argon gas, air, helium) stream removes molten
Agent is washed resin with the dichloromethane of 100ml and pyridine (or chloroform, toluene equal solvent) respectively later, is directly carried out down successively
Single step reaction.
In embodiment one, chloromethyl resin may be replaced by polystyrene-benzene divinyl crosslinked resin, polyacrylamide
Amine, polyethylene-glycols resin, carboxy resin, amino resins, hydrazides type resin etc..
According to functional group's difference of resin, the amount ratio of 7-ACA and resin is adjusted.Such as：Using polystyrene type,
When the resin of polyethylene kind structure, the dosage of 7-ACA is 5-20g：100g resins.Using carboxy resin, amino resins, hydrazides type
When resin, the dosage of 7-ACA is 15-30g：100g resins.
Solvent can also be dichloromethane, DMSO, chloroform：DMF(50/50)、DMSO：DMF (10/90) etc., the solvent
Dosage be subject to and submerge resin.
Bridge reaction mode can be react at room temperature, be stirred to react, heating reflux reaction, microwave reaction, ultrasonic reaction
Etc. mode.
Embodiment two：Prepare the ceftriaxone of solid phase bridge joint
A. in glaze glass column, 30g 6- hydroxyl -3- sulfydryl -2- methyl-1s are added, the acetonitrile of 2,4- triazine -5- ketone is (just
The state being completely dissolved well) solution, it is heated to 50 DEG C under nitrogen protection, 56g catalyst boron trifluorides are added, stirs lower reaction
2h uses N after reaction2(gases such as argon gas, air, helium) stream remove solvent, later respectively use 100ml dichloromethane and
Pyridine (or chloroform, toluene equal solvent) washs resin successively, directly carries out next step reaction.
In this step, 6- hydroxyls -3- sulfydryls -2- methyl-1s, it is it that 2,4- triazine -5- ketone, which may be replaced with 3,
The triaizine compounds of the leaving group of his sulfur-bearing, such as：
X：For chlorine, iodine, bromine, ester group, the isostructural leaving group of acid halide group.
The dosage of the triaizine compounds is：The molar ratio of 7-ACA and triaizine compounds is 1:1 or 1:2 or 1:2.5 or 1:3
Or 1:3.5 or 1:4 or 1:5 etc., according to solubility of the triaizine compounds in different solvents, the triaizine compounds solution of addition
Concentration can be 35-90% differ, when the solubility of triaizine compounds is high, the more a height of 75-90% of concentration, when triazine chemical combination
When the solubility of object is low, relatively low concentration is 35-74%.
According to the difference of system environment, reaction condition, which can also carry out under the following conditions：40 DEG C, 5 hours (s:
DMF, X：CH3COO-)；40 DEG C, 4 hours (s:TCM, X:H)；50 DEG C, 3 hours (s:DMSO, X:H)；60 DEG C, 2 hours (s:THF,
X:H)；70 DEG C, 1.5 hours (s:ACN, X:ClCO-)；80 DEG C, 1 hour (s:DCM, X:I).
B. S1 [dichloromethane (75ml)-ethyl alcohol (10ml)-triethylamine (8g)-water (70ml)] solution, nitrogen are added in column
Cooling is stirred under gas shielded, and 25g 2- (2- amino -4- thiazolyls) -2- (methoxy imido is added under -5 DEG C (- 15 DEG C -0 DEG C)
Base) acetic acid thioxothiazole ester, keep -5 DEG C of reaction 6h.N is used after reaction2(gases such as argon gas, air, helium) stream removes molten
Agent is washed resin with the dichloromethane of 100ml and pyridine (or chloroform, toluene equal solvent) respectively later, is directly carried out down successively
Single step reaction.
Reaction dissolvent can also be S2 [50ml DCM：5ml THF:10gTMG:100ml H2O] or S3 [70ml TCM：
15ml DEE:15g urea:50ml H2O] or S4 [50ml DMF：2ml DMK:20gTEA:70ml H2O] or S5 [80ml TCM：
5ml EtOH:30g urea:40ml H2O] or S6 [50ml DMSO：2ml EA:20gTEA:70ml H2O] or S7 [80ml DCE：
5ml MeOH:25gPy:5gTMG:80ml H2O] etc.；
In this step, 2- (2- amino -4- thiazolyls) -2- (methoxyimino) acetic acid thioxothiazole ester can also by for
It is changed to the thiazole of other leaving groups, such as：
Y：For chlorine, iodine, bromine ,-OR (R is the alkyl that carbon atom is not more than 4), nitro, cyano, amino,
The isostructural leaving group of hydroxyl.
The dosage of the acylating reagent is：The molar ratio of 7-ACA and acylating reagent is 1:1 or 1:2 or 1:2.5 or 1:3 or 1:
3.5 or 1:4 or 1:5 etc..
According to the difference of system environment, reaction condition, which can also carry out under the following conditions：- 15 DEG C, 10 hours
(S2, Y：CH3O-)；- 10 DEG C, 8 hours (S3, Y:I)；- 5 DEG C, 7 hours (S4, Y:NO2)；0 DEG C, 6 hours (S5, Y:Cl)；10 DEG C,
5.5 hours (S6, Y:C2H5O-)；15 DEG C, 5 hours (S1, X:-OH)；20 DEG C, 4 hours (S7, X:CN)；25 DEG C, 3 hours (S1, X:
NH2)。
Embodiment three：Ceftriaxone is reacted with solid phase disengaging
Resin is transferred in reaction bulb, is added in 100ml dichloromethane and 20ml trifluoroacetic acid solutions, 2h is stirred at room temperature
After (according to different solvents, its reaction temperature can also be 1 hour or 1.5 hours or 2.5 hours or 3 hours), reaction mixture
- 20 DEG C are cooled to, 5ml trifluoromethanesulfonic acids is added with stirring, is warmed to room temperature after reaction 2h and continues to stir 6h, filtering is removed in vacuum
Organic solvent.
Obtained solid is dissolved in 100ml tetrahydrofurans and ethyl acetate solution, with sodium acetate (organic sodium such as sodium formate
Salt) extraction with aqueous solution, the washing of gained aqueous layer with ethyl acetate, then with activated alumina column chromatography separating purification, collection is containing mesh
Mark the elution efflux of compound.Acetone is added into eluent, is cooled to 15 DEG C, growing the grain 1h, continues drop and acetone is slowly added dropwise
Solution is cooled to 0 DEG C of stirring growing the grain 1h, filters, wash, dry.Obtain ceftriaxone sodium crystal.Overall yield of reaction is 90%,
Purity is 99.5%.
Reaction system can also be：DMSO：HF(10:Or TCM 3)：TFA(10:Or Tol 2.5)：TFA(10:1.5) or
DMF：TFA(10：1) etc..
Claims (11)
1. a kind of solid-phase synthesis of Ceftriaxone Sodium, it is characterised in that：
Raw material A is bridged on solid phase carrier, is substituted, after amidation process, solid phase carrier is detached from and Ceftriaxone Sodium is made；
Wherein, the raw material A is such as lower structure compound represented：
The solid phase carrier is chloromethyl resin；
Specific process step is as follows：
Step 1: raw material A and solid phase carrier are in organic solvent, react 0.5-10 hours, obtains at a temperature of 25-180 DEG C
Bridge product one；
Step 2: after triazine heterocyclic compound is added, 40-80 DEG C is heated in the case of protecting gas shielded；
Step 3: catalyst one is added, catalysis reaction 1-5 hours obtains bridge joint product two；
Step 4: the mixed solution of organic solvent and organic base is added, 0 DEG C or less is cooled in the case of protecting gas shielded；
Step 5: amidation reagent is added, at a temperature of -15 DEG C -35 DEG C, react 3-10 hours, obtains bridge joint product three；
Step 6: the mixed solution of organic solvent and acid is added, reacted 1-3 hours at a temperature of 10-35 DEG C；
Step 7: cooling reaction system to -15 DEG C hereinafter, be added catalyst two react 1-3 hours after, be warming up to 10-35 DEG C after
Continuous reaction 3-10 hours；
Step 8: post-treated acquisition target product.
2. a kind of solid-phase synthesis of Ceftriaxone Sodium as described in claim 1, it is characterised in that：
The triazine heterocyclic compound is such as lower structure compound represented：
Wherein, R1 is selected from hydrogen, halogen, ester group, alkoxy, acid halide group, hydroxyl.
3. a kind of solid-phase synthesis of Ceftriaxone Sodium as described in claim 1, it is characterised in that：
The amidation reagent is such as lower structure compound represented：
Wherein, the R2 is selected from hydrogen, halogen, ester group, alkoxy, nitro, hydroxyl, amino.
4. a kind of solid-phase synthesis of Ceftriaxone Sodium as described in claim 1, it is characterised in that：
It is described Step 1: after the completion of three and five reaction, by the solvent in air-blowing method discharge system, and by least once
The mode of organic solvent elution obtains bridge joint product one, bridge joint product two and bridge joint product three.
5. a kind of solid-phase synthesis of Ceftriaxone Sodium as described in claim 1, it is characterised in that：
The organic solvent is selected from the halogenated hydrocarbons of liquid, amide, sulfur-bearing organic solvent, alkyl nitrile, alcohols, esters, ethers, heteroaryl
It is one or more of in class, aromatic solvents；
The catalyst one is selected from organic boron series catalysts；
Organic base is selected from organic amine compound, amides compound, alkoxide, metal alkyl lithium compound, nitrogenous heterocycle and spreads out
One or more of biology；
The acid and catalyst two be selected from trifluoroacetic acid, hydrofluoric acid, organic sulfonic acid, one or more of containing silica reagent.
6. a kind of solid-phase synthesis of Ceftriaxone Sodium as described in claim 1, it is characterised in that：
The organic solvent is selected from dichloromethane, chloroform, dimethylformamide, dimethyl sulfoxide (DMSO), acetonitrile, methanol, ethyl alcohol, third
One or more of alcohol, pyridine, tetrahydrofuran, acetone, ether, ethyl acetate, methyl acetate, toluene, benzene, dioxane.
7. a kind of solid-phase synthesis of Ceftriaxone Sodium as described in claim 1, it is characterised in that：
The catalyst one is selected from one or more of boron trihalides, alkylboronic acids, the boric acid of aromatics, organic boric acid ester.
8. a kind of solid-phase synthesis of Ceftriaxone Sodium as described in claim 1, it is characterised in that：
Organic base is selected from triethylamine, one kind in tetramethylguanidine, urea, sodium methoxide, sodium ethoxide, potassium tert-butoxide, tert-butyl lithium or
It is several.
9. a kind of solid-phase synthesis of Ceftriaxone Sodium as described in claim 1, it is characterised in that：
The acidity of the acid is better than the acidity of the catalyst two.
10. a kind of solid-phase synthesis of Ceftriaxone Sodium as described in claim 1, it is characterised in that：
The dosage of the raw material A is the 5-30% of the quality of solid phase carrier；
The molar ratio of the triazine heterocyclic compound and raw material A is 1-5:1；
The molar ratio of the catalyst one and raw material A is 1-3:1；
The dosage of the organic base is the 1-20% of solvent total weight in step 4；
The dosage of the acid is the 10-30% of total solvent volume in step 6；
The molar ratio of the amidation reagent and raw material A is 1-5:1.
11. a kind of solid-phase synthesis of Ceftriaxone Sodium as described in claim 1, it is characterised in that：
The process of the post-processing is：
1, it by the product of step 7, filters after removing solid insoluble, except solvent obtains solid crude product；
2, after crude product being dissolved in organic solvent, it includes production to wash and extract through sodium-salt aqueous solution at least once and extract liquor
The solution layer of object；
3, after crossing acid column at least once, eluent is collected；
4, the crystal of target product is obtained by being added into eluent after polarity poor solvent.
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| WO2002085914A2 (en) * | 2001-04-19 | 2002-10-31 | Bioferma Murcia, S.A. | ENZYMATIC PROCESS FOR PREPARING CEPHALOSPORANIC ACID DERIVATIVES USING α-KETOACID DERIVATIVES |
| 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 |
| CN105061472A (en) * | 2015-08-18 | 2015-11-18 | 齐鲁安替（临邑）制药有限公司 | One-pot synthesis method of ceftriaxone sodium |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000063214A1 (en) * | 1999-04-15 | 2000-10-26 | Biochemie Gesellschaft M B H | Beta-lactam production |
| WO2002085914A2 (en) * | 2001-04-19 | 2002-10-31 | Bioferma Murcia, S.A. | ENZYMATIC PROCESS FOR PREPARING CEPHALOSPORANIC ACID DERIVATIVES USING α-KETOACID DERIVATIVES |
| 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 |
| CN105061472A (en) * | 2015-08-18 | 2015-11-18 | 齐鲁安替（临邑）制药有限公司 | One-pot synthesis method of ceftriaxone sodium |
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