CN105017285B - A kind of synthesis technique of cephalo-type anti-infectives - Google Patents
A kind of synthesis technique of cephalo-type anti-infectives Download PDFInfo
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- CN105017285B CN105017285B CN201510398276.4A CN201510398276A CN105017285B CN 105017285 B CN105017285 B CN 105017285B CN 201510398276 A CN201510398276 A CN 201510398276A CN 105017285 B CN105017285 B CN 105017285B
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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
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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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- 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
- C07D501/12—Separation; Purification
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Abstract
The present invention relates to a kind of synthesis technique of new cephalo-type anti-infectives, use with 3, the acetic acid of 5 dichloro-4,4 pyridone 1 and the thiadiazoles of 2 sulfydryl, 5 methyl 1,3,4 are directly successfully prepared cefazedone sodium for the thioester compound (formula III) of Material synthesis with 7 ACA single step reactions.The synthetic method of the present invention not only simplify operating procedure, make working condition milder, the generation of reduction accessory substance, production technology simpler, and all improved a lot on product yield and purity, reduce cost, environmental pollution is small, with the more preferable feature of environmental protection, technique is set to meet the requirement of industrialization.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, and in particular to a kind of conjunction of new cephalo-type anti-infectives cefazedone sodium
Into technique.
Background technology
Cefazedone sodium (Cefazedone) belongs to first generation injection cephalosporin analog antibiotic, to various gram-positive bacterias and
Gram-negative bacteria includes staphylococcus aureus, streptococcus, the curative effect of enterococcus and is superior to similar drugs-cephazoline
And cefoxitin, drug resistance is also substantially better than the latter, is classical broad-spectrum antibiotic, and has a broad antifungal spectrum, clinical practice is extensive.In state
The clinical research test result for amounting to 732 patients that outer 7 countries, 35 hospitals participate in shows that Cefazedone is blue for leather
Urinary system infection contamination, respiratory tract infection, surgery-skin infection, gynecological infection, biliary tract-abdomen caused by formula positive bacteria and negative bacterium
Portion's infection, various complexity are infected and in the efficient more than 90% of neonatal preventive and therapeutic action.
The chemical name of cefazedone sodium is (6R, 7R) -7- (2- (chloro- 4- oxos -1 (the 4H)-pyridine radicals of 3,5- bis-) acetyl
Amino) -3- (((5- methyl isophthalic acids, 3,4- thiadiazoles -2- bases) sulphur) methyl) -8- oxo -5- thia -1- azabicyclos [4.2.0]
Oct-2-ene -2- sodium formates, its molecular formula is：C18H14Cl2N5NaO5S3；Its structural formula is：
The preparation method of prior art synthesis cefazedone sodium has number of ways, disclosed in United States Patent (USP) US5945414
The synthetic method of Cefazedone, is first raw material with mercaptan in aqueous under the conditions of 90 DEG C of the temperature by glutaryl 7-ACA
Reaction 2-10 hours, the compound of generation obtains target product by deacylated.Raw materials technology glutaryl 7-ACA is difficult purchase
Obtain, it is necessary to which Deprotection, complex steps, reaction temperature is high, accessory substance is more, product yield and purity difference, be not suitable for industrialization
Production.
Patent DE 2345402 reports Cefazedone synthesis technique：The 7-amino-cephalosporanic acid tert-butyl ester (1) and (2) 3,
The chloro- 4- pyridones -1- acetic acid of 5- bis- obtains the tertiary fourth of 7- cephalosporanic acids by dicyclohexylcarbodiimide (DCC) in dichloromethane
Ester (3), corresponding free acid (4) is obtained with trifluoroacetic acid hydrolysis, finally with 5- methyl isophthalic acids, and 3,4- thiadiazoles -2- mercaptan (V) lead to
Cross NaHCO3Obtained in water and the acetone mixture condensation reaction of heat；Its synthesis route is：
The step of synthetic route of above-mentioned Cefazedone, is longer, uses the big trifluoroacetic acid of expensive, toxicity, DCC etc.
Reagent, course of reaction is complicated, and the yield of final products is low so that the cost of whole building-up process is higher.
The chemical preparation process that Cefazedone is carried out by initiation material of 7-ACA conventional at present mainly has two kinds：
The first route is：With the chloro- 4- pyridones -1- acetic acid of 3,5- bis- for initiation material, with trichloro-acetic chloride into acid anhydrides
Replace intermediates with the 7-ACA of silanization formation 7- afterwards, then be condensed in the basic conditions with 1- methyl thiadiazoles -5- mercaptan
To Cefazedone, specific synthetic route is as follows：
Second of route：7-ACA first occurs sulphur substitution reaction with 1- methyl thiadiazoles -5- mercaptan and generated in 3- substitutions
Mesosome, then Cefazedone is generated with the chloro- 4- pyridones -1- acetic acid nucleophilic displacement of fluorine of 3,5- bis-, specific synthetic route is as follows：
In above two process route, route one synthesis mainly since 7-ACA 7- positions, and route two be from
7-ACA 3- positions start synthesis, synthesis Cefazedone yield (71.5%) a little higher than route one (60%) of route two, but route
Two weak point is that the accessory substance that 1- methyl thiadiazoles -5- mercaptan reacts with 7-ACA is adjoint into end-product always, and very
Difficulty finds suitable purification process, and so it synthesizes cost and will accordingly improved, and is not suitable for industrialization large-scale production.
In the prior art, the method for synthesizing cefazedone sodium, it is low that generally existing yield, and product color is differential and industrial production
The shortcomings of cost is high.The difficulty of technique causes the costliness of preparation price, and financial burden, and building-up process are caused to drug user
The middle chemical reagent for having used high pollution, it is larger to environmental disruption.It is badly in need of being improved synthesis technique at present, meets industry
Change production requirement.
The content of the invention
An object of the present invention is to provide that a kind of working condition gentle, simple production process, side reaction be few, product yield
The synthetic method of high new cephalo-type anti-infectives cefazedone sodium with purity.
The present invention is realized using following technical scheme：
A kind of synthesis technique of new cephalo-type anti-infectives, it is characterised in that comprise the following steps：
(1) with the chloro- 4- pyridones -1- acetic acid (formula I) of 3,5- bis- and 2- sulfydryl -5- methyl isophthalic acids, 3,4- thiadiazoles (formula II)
For the preparation of the thioester compound (formula III) of Material synthesis：
By the chloro- 4- pyridones -1- acetic acid (formula I) of 3,5- bis- and 2- sulfydryl -5- methyl isophthalic acids, 3,4- thiadiazoles (formula II) is dissolved in
In organic solvent, organic base is added, reaction 1 hour is stirred at room temperature, then the organic solvent solution dissolved with catalyst, 1- is slowly added dropwise
Below completion of dropping in 2 hours, 20-25 DEG C of temperature control stirring reaction 1-2 hours, filtering, 10 DEG C of filtrate cooling down, knot is separated out
Crystalline substance, suction filtration is dried, produces thioester compound (formula III)；
(2) preparation of cefazedone sodium (formula IV)：
Under the protections of nitrogen, 7-ACA and sodium acid carbonate are added to the in the mixed solvent of water and ethanol, are stirred to dissolve,
The thioester compound (formula III) obtained by step (1) is added, control temperature is reacted, then adjusts pH value with sodium acid carbonate；It is living
Property carbon decoloring, crystallize, filter, wash, dry, obtain product cefazedone sodium (formula IV)；Its synthetic route is as follows：
It is preferred that, in step (1), organic solvent used is that the one or more in dichloromethane, acetone, tetrahydrofuran are mixed
Close.
It is preferred that, in step (1), the catalyst is isopropyl chlorocarbonate or triethyl phosphite；2- sulfydryl -5- first
The molar ratio of the chloro- 4- pyridones -1- acetic acid of base -1,3,4- thiadiazoles, 3,5- bis- and catalyst is 1.05~1.10：1.00：
1.10-1.20。
It is preferred that, in step (1), the organic base is the one or more of triethylamine or pyridine.Further,
When organic base is triethylamine or pyridine, the molar ratio of organic base and the chloro- 4- pyridones -1- acetic acid of 3,5- bis- is 1.0-1.2：
1；When the mixed liquor that organic base is triethylamine and pyridine, mole of triethylamine, pyridine and the chloro- 4- pyridones -1- acetic acid of 3,5- bis-
Ratio is 0.4-0.60：0.08-0.1：1.
It is preferred that, in step (2), it is 6-8 to adjust pH value with sodium acid carbonate, it is further preferred that regulation pH value is 7.
It is preferred that, in step (2), described reaction temperature is 30-50 DEG C, and the reaction time is 2-4 hours.
It is preferred that, in step (2), the mol ratio of the 7-ACA and thioester compound (formula III) is 1：1.0-1.1.
It is preferred that, the crystallization processes in step (2) are：Activated carbon is added in reaction solution, it is 30-40 to keep filtrate temperature
DEG C stirring decolourize, then cross filter out activated carbon；Then temperature is controlled to add a certain amount of acetone to muddiness, stirring 2 for 10-20 DEG C
Hour, crystallization is separated out, 0-5 DEG C is cooled to 5-10 DEG C/h of rate of temperature fall, is then kept stirring for 80-120 revs/min of speed
Clock stirring and crystallizing, growing the grain 1-3 hours；Filtering, filter cake is washed with ethyl acetate, and less than 40 DEG C vacuum drying obtain product cephalo west
Ketone sodium.
Relative to prior art, the invention has the advantages that：
(1) present invention improves over the synthesis technique of cefazedone sodium, with the chloro- 4- pyridones -1- acetic acid of 3,5- bis- and 2- mercaptos
Base -5- methyl isophthalic acids, 3,4- thiadiazoles is directly successfully prepared for the thioester compound (formula III) of Material synthesis with 7-ACA single step reactions
Cefazedone sodium.The synthetic method of the present invention not only simplify operating procedure, makes working condition milder, reduces accessory substance hair
Raw, production technology is simpler, and is all improved a lot on product yield and purity, and product purity is more than 99.8%, always
Yield reduces cost more than 88%, environmentally safe, with the more preferable feature of environmental protection, technique is met wanting for industrialization
Ask.
(2) examinations of expensive toxicity greatly such as TFAA or DCC are used in the method for synthesis thioesters in the prior art
Agent is as condensing agent, and the present invention is improved condensing agent and base catalyst, using cheap isopropyl chlorocarbonate
Or triethyl phosphite is condensing agent, passes through the control to course of reaction condensing agent rate of addition；Using three necessarily matched
Ethamine and pyridine optimize the proportioning of triethylamine and pyridine as base catalyst；Also by comparing being reacted between reactant
The optimization of example, substantially reduces product cost, and post processing is easy, and one-step reaction yield is up to more than 96%, purity more than 99%；Together
When side reaction greatly reduce, simplify the purification process of intermediate or final product, improve product in whole course of reaction
Yield, and purity also accordingly improves.
Embodiment
Technical scheme is further described with embodiment below, it will help to the technical side of the present invention
Advantage, the effect of case, which have, further to be understood, and embodiment does not limit protection scope of the present invention, protection scope of the present invention by
Claim is determined.
Embodiment 1：
(1) preparation of thioester compound (formula III)：
In dry reaction bulb, tetrahydrofuran 200ml is added, the chloro- 4- pyridones -1- acetic acid 22.2g of 3,5- bis- are added
(formula I, 0.1mol) and 2- sulfydryl -5- methyl isophthalic acids, 3,4- thiadiazoles 14.55g (formula II, 0.11mol), stirring adds three second
Amine 12.2g (0.12mol), is stirred at room temperature reaction 1 hour, then the tetrahydrofuran dissolved with catalyst triethyl phosphite is slowly added dropwise
Solution (triethyl phosphite 20g is dissolved in 50ml tetrahydrofuran, 0.12mol), is dripped off in 1 hour, and 20-25 DEG C of stirring of temperature control is anti-
Answer 1 hour, filter, filtrate cooling down separates out crystallization to less than 10 DEG C, and suction filtration, less than 40 DEG C vacuum drying produce thioesterification
Compound 32.7g (formula III, 0.097mol), yield is that 97%, HPLC purity is 99.5%.
(2) preparation of cefazedone sodium (formula IV)：
Under the protection of nitrogen, by 7-ACA 24.5g (0.09mol) and sodium acid carbonate 7.6g (0.09mol) add water and
In the mixed solvent (water 100ml and ethanol 200ml) of ethanol, it is stirred to dissolve, adds the thioester compound obtained by step (1)
30.3g (formula III, 0.09mol), 40-50 DEG C of stirring reaction of control temperature 2 hours, then adjust pH value with 5% sodium bicarbonate solution
To 6.5；Activated carbon is added in reaction solution, it is that 30-40 DEG C of stirring is decolourized 0.5 hour to keep filtrate temperature, and filtering removes activity
Charcoal；Then it is 10-20 DEG C of addition 300ml acetone to muddiness to control temperature, stirs 2 hours, separates out crystallization, with 5-10 DEG C/it is small
When rate of temperature fall be cooled to 0-5 DEG C, be then kept stirring for 80-120 revs/min of stirring and crystallizing of speed, growing the grain 1-3 hours；Cross
Filter, wash filter cake with a small amount of ethyl acetate, and less than 40 DEG C are dried in vacuo, obtain product cefazedone sodium 48.0g (formula IV,
0.084mol), yield is that 93.5%, HPLC purity is 99.9%.
Embodiment 2：
(1) preparation of thioester compound (formula III)：
In dry reaction bulb, tetrahydrofuran 180ml is added, the chloro- 4- pyridones -1- acetic acid 22.2g of 3,5- bis- are added
(formula I, 0.1mol) and 2- sulfydryl -5- methyl isophthalic acids, 3,4- thiadiazoles 14.55g (formula II, 0.11mol), stirring adds three second
Amine 6.1g (0.06mol), pyridine 0.8g (0.01mol), are stirred at room temperature reaction 1 hour, then be slowly added dropwise dissolved with catalyst chloromethane
The tetrahydrofuran solution (isopropyl chlorocarbonate 14.7g is dissolved in 50ml tetrahydrofuran, 0.12mol) of isopropyl propionate, drips in 1 hour
It is complete, 20-25 DEG C of stirring reaction of temperature control 1 hour, filtering, filtrate cooling down to less than 10 DEG C, separate out crystallize, suction filtration, 40 DEG C with
Lower vacuum drying, produces thioester compound 32.8g (formula III, 0.0966mol), and yield is that 96.6%, HPLC purity is 99.2%.
(2) preparation of cefazedone sodium (formula IV)：
Under the protection of nitrogen, by 7-ACA 24.5g (0.09mol) and sodium acid carbonate 7.6g (0.09mol) add water and
In the mixed solvent (water 150ml and ethanol 150ml) of ethanol, it is stirred to dissolve, adds the thioester compound obtained by step (1)
30.3g (formula III, 0.09mol), 40-50 DEG C of stirring reaction of control temperature 4 hours, then adjust pH value with 5% sodium bicarbonate solution
To 6.5；Activated carbon is added in reaction solution, it is that 30-40 DEG C of stirring is decolourized 0.5 hour to keep filtrate temperature, and filtering removes activity
Charcoal；Then it is 10-20 DEG C of addition 300ml acetone to muddiness to control temperature, stirs 2 hours, separates out crystallization, with 5-10 DEG C/it is small
When rate of temperature fall be cooled to 0-5 DEG C, be then kept stirring for 80-120 revs/min of stirring and crystallizing of speed, growing the grain 1-3 hours；Cross
Filter, wash filter cake with a small amount of ethyl acetate, and less than 40 DEG C are dried in vacuo, obtain product cefazedone sodium 48.0g (formula IV,
0.084mol), yield is that 93.5%, HPLC purity is 99.8%.
Embodiment 3：
(1) preparation of thioester compound (formula III)：
In dry reaction bulb, dichloromethane 200ml is added, the chloro- 4- pyridones -1- acetic acid 33.3g of 3,5- bis- are added
(formula I, 0.15mol) and 2- sulfydryl -5- methyl isophthalic acids, 3,4- thiadiazoles 20.8g (formula II, 0.1575mol), stirring adds three
Ethamine 6.1g (0.06mol), pyridine 0.95g (0.012mol), are stirred at room temperature reaction 1 hour, then be slowly added dropwise dissolved with catalyst
The dichloromethane solution (triethyl phosphite 14.7g is dissolved in 50ml dichloromethane) of triethyl phosphite, is dripped off in 1 hour,
Below 20-25 DEG C of stirring reaction of temperature control 1 hour, filtering, 10 DEG C of filtrate cooling down, crystallization, suction filtration, less than 40 DEG C vacuum are separated out
Dry, produce thioester compound 49.3g (formula III, 0.1452mol), yield is that 96.8%, HPLC purity is 99.0%.
(2) preparation of cefazedone sodium (formula IV)：
Under the protection of nitrogen, by 7-ACA 32.7g (0.12mol) and sodium acid carbonate 10.5g (0.12mol) add water and
In the mixed solvent (water 200ml and ethanol 200ml) of ethanol, it is stirred to dissolve, adds the thioester compound obtained by step (1)
44.4g (formula III, 0.132mol), 40-50 DEG C of control temperature carries out reaction 4 hours, then adjusts pH value with 5% sodium bicarbonate solution
To 7；Activated carbon is added in reaction solution, it is that 30-40 DEG C of stirring is decolourized 0.5 hour to keep filtrate temperature, and filtering removes activated carbon；
Then control the acetone that temperature is 10-20 DEG C of addition 500ml to muddiness, stir 2 hours, crystallization is separated out, with 5-10 DEG C/h
Rate of temperature fall is cooled to 0-5 DEG C, is then kept stirring for 80-120 revs/min of stirring and crystallizing of speed, growing the grain 1-3 hours；Filtering, is used
A small amount of ethyl acetate washing filter cake, less than 40 DEG C vacuum drying obtain product cefazedone sodium 64.2g (formula IV, 0.11256mol),
Yield is that 93.8%, HPLC purity is 99.8%.
Embodiment 4：
(1) preparation of thioester compound (formula III)：
In dry reaction bulb, the chloro- 4- pyridones -1- acetic acid 22.2g of addition acetone 200ml, addition 3,5- bis- (formula I,
0.1mol) with 2- sulfydryl -5- methyl isophthalic acids, 3,4- thiadiazoles 14.3g (formula II, 0.108mol), stirring adds triethylamine 5.0g
(0.05mol), pyridine 0.8g (0.01mol), is stirred at room temperature reaction 1 hour, then be slowly added dropwise dissolved with catalyst phosphorous triethylenetetraminehexaacetic acid
The acetone soln (triethyl phosphite 18.3g is dissolved in 60ml acetone, 0.11mol) of ester, is dripped off, 20-25 DEG C of temperature control in 1 hour
Below stirring reaction 1 hour, filtering, 10 DEG C of filtrate cooling down, crystallization is separated out, suction filtration, less than 40 DEG C vacuum drying produce sulphur
Ester compounds 33.0g (formula III, 0.0936mol), yield is that 97.0%, HPLC purity is 98.9%.
(2) preparation of cefazedone sodium (formula IV)：
Under the protection of nitrogen, by 7-ACA 24.5g (0.09mol) and sodium acid carbonate 7.6g (0.09mol) add water and
In the mixed solvent (water 150ml and ethanol 150ml) of ethanol, it is stirred to dissolve, adds the thioester compound obtained by step (1)
33.3g (formula III, 0.099mol), 40-50 DEG C of control temperature carries out reaction 2 hours, then adjusts pH value with 5% sodium bicarbonate solution
To 6.0；Activated carbon is added in reaction solution, it is that 30-40 DEG C of stirring is decolourized 0.5 hour to keep filtrate temperature, and filtering removes activity
Charcoal；Then it is 10-20 DEG C of addition 320ml acetone to muddiness to control temperature, stirs 2 hours, separates out crystallization, with 5-10 DEG C/it is small
When rate of temperature fall be cooled to 0-5 DEG C, be then kept stirring for 80-120 revs/min of stirring and crystallizing of speed, growing the grain 1-3 hours；Cross
Filter, wash filter cake with a small amount of ethyl acetate, and less than 40 DEG C are dried in vacuo, obtain product cefazedone sodium 47.9g (formula IV,
0.08397mol), yield is that 93.3%, HPLC purity is 99.9%.
Claims (9)
1. a kind of synthesis technique of cephalo-type anti-infectives, it is characterised in that comprise the following steps：
(1) preparation of the thioester compound of formula III：
By the chloro- 4- pyridones -1- acetic acid of the 3,5- bis- of formula I and the 2- sulfydryl -5- methyl isophthalic acids of formula II, 3,4- thiadiazoles is dissolved in organic
In solvent, organic base is added, reaction 1 hour is stirred at room temperature, then the organic solvent solution dissolved with catalyst is slowly added dropwise, 1-2 is small
When interior completion of dropping, 20-25 DEG C of temperature control stirring reaction 1-2 hours, filtering, filtrate cooling down to less than 10 DEG C, separate out crystallize,
Suction filtration, dries, produces the thioester compound of formula III；
(2) preparation of the cefazedone sodium of formula IV：
Under the protection of nitrogen, 7-ACA and sodium acid carbonate are added to the in the mixed solvent of water and ethanol, are stirred to dissolve, is added
The thioester compound of formula III obtained by step (1), control temperature is reacted, then adjusts pH value with sodium acid carbonate；Activated carbon
Decolourize, crystallize, filter, wash, dry, obtain the cefazedone sodium product of formula IV；Its synthetic route is as follows：
In step (1), the catalyst is isopropyl chlorocarbonate or triethyl phosphite；2- sulfydryl -5- methyl isophthalic acids, 3,4- thiophenes
The molar ratio of the chloro- 4- pyridones -1- acetic acid of diazole, 3,5- bis- and catalyst is 1.05~1.10：1.00：1.10-1.20.
2. synthesis technique according to claim 1, it is characterised in that：In step (1), organic solvent used is dichloromethane
One or more of mixing in alkane, acetone, tetrahydrofuran.
3. synthesis technique according to claim 1, it is characterised in that：In step (1), the organic base is triethylamine and pyrrole
The one or more of pyridine.
4. synthesis technique according to claim 1, it is characterised in that：In step (1), the organic base is triethylamine or pyrrole
The molar ratio of pyridine, organic base and the chloro- 4- pyridones -1- acetic acid of 3,5- bis- is 1.0-1.2：1；Or organic base be triethylamine with
The mixed liquor of pyridine, the molar ratio of triethylamine, pyridine and the chloro- 4- pyridones -1- acetic acid of 3,5- bis- is 0.4-0.60：0.08-
0.1：1.
5. synthesis technique according to claim 1, it is characterised in that：In step (2), it is 6- to adjust pH value with sodium acid carbonate
8。
6. synthesis technique according to claim 1, it is characterised in that：It is 7 with sodium acid carbonate regulation pH value in step (2).
7. synthesis technique according to claim 1, it is characterised in that：In step (2), described reaction temperature is 30-50
DEG C, the reaction time is 2-4 hours.
8. synthesis technique according to claim 1, it is characterised in that：In step (2), the thioesters of the 7-ACA and formula III
The mol ratio of compound is 1：1.0-1.1.
9. synthesis technique according to claim 1, it is characterised in that：Crystallization processes in step (2) are：By activated carbon plus
Enter in reaction solution, keep filtrate temperature to be 30-40 DEG C and stir decolouring 0.5-1 hours, then cross and filter out activated carbon；Then temperature is controlled
Spend and add a certain amount of acetone to muddiness for 10-20 DEG C, stir 2 hours, crystallization is separated out, with 5-10 DEG C/h of rate of temperature fall
0-5 DEG C is cooled to, 80-120 revs/min of stirring and crystallizing of speed, growing the grain is then kept stirring for 1-3 hours；Filtering, uses ethyl acetate
Filter cake is washed, less than 40 DEG C vacuum drying obtain the cefazedone sodium product of formula IV.
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| KR100663239B1 (en) * | 2004-12-24 | 2007-01-02 | 주식회사 엔지켐 | Purification method of cefazedone free acid |
| CN101584671B (en) * | 2009-07-17 | 2011-03-16 | 山东罗欣药业股份有限公司 | Cefazedone sodium medicament powder injection and method for synthesizing raw medicine of Cefazedone sodium |
| CN104230958A (en) * | 2014-08-22 | 2014-12-24 | 赵明亮 | Method for preparing cefazedone |
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