CN105440054B - A kind of technique preparing cefathiamidine - Google Patents
A kind of technique preparing cefathiamidine Download PDFInfo
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- CN105440054B CN105440054B CN201510592278.7A CN201510592278A CN105440054B CN 105440054 B CN105440054 B CN 105440054B CN 201510592278 A CN201510592278 A CN 201510592278A CN 105440054 B CN105440054 B CN 105440054B
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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
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/28—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by an aliphatic carboxylic acid, which is substituted by hetero 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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- Cephalosporin Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of techniques preparing cefathiamidine, more particularly to a kind of technique preparing high-purity cefathiamidine.Preparation method is：Preparation method is：In acetyl bromide 7ACA and N, in the reaction of N ' di-isopropyl thioureas or after reaction, the inorganic salt solution of water or water is added as secondary solvent；After reaction, cooling, dropwise addition crystallization solvent, suction filtration obtain cefathiamidine crude product；High-purity cefathiamidine is obtained after purifying vacuum drying again.Preparation method through the invention, the residual of impurity in cefathiamidine can be effectively reduced, and the content of acetyl bromide 7ACA and high-molecular compound impurity can be made to be reduced to 0.1% or less or fully erased, the residual of other cefathiamidine impurity can be reduced to 0.2% or less.
Description
Technical field
The invention belongs to chemicals to synthesize field, be related to the preparation method of high-purity cefathiamidine, more particularly to one
Kind prepares cephalo sulphur using a kind of of high-purity cefathiamidine that acetyl bromide -7ACA and high-molecular compound make impurity content reduce
The technique of amidine.
Background technology
Cefathiamidine (Cefathiamidine) is that had by Shanghai Institute of Pharmaceutical Industry and Community in Baiyunshan, Guangzhou pharmacy share
The beta-lactam antibiotic of the common independent research of limit company has most of gram positive bacteria, part Glan negative bacterium relatively strong
Antibacterial action, especially have unique curative effect to enterococcus.It clinically uses extensively, is mainly used for gold-coloured staphylococci, pneumonia
Respiratory tract infection, infection of biliary tract caused by coccus and streptococcus.
Structural formula is as follows：
Currently, production cefathiamidine often uses the intermediate acetyl bromide -7ACA that are reacted with bromoacetyl bromide of 7ACA, then with N,
The reaction of N '-di-isopropyl thioureas generates cefathiamidine crude product, and crude product is further refining to obtain the cefathiamidine for meeting pharmacopoeial requirements.
The preparation process reaction equation is as follows：
Currently, usually acetyl bromide -7ACA and N, N '-di-isopropyl thiourea is in dichloromethane, in organic bases triethylamine
Under conditions of, reaction generates cefathiamidine.But the residual quantity of acetyl bromide -7ACA is very high, is difficult to by the methods of impregnating, washing
Acetyl bromide -7ACA impurity is effectively removed, recrystallization also is difficult to remove, to influence the purity of cefathiamidine.
Under normal conditions, the major impurity contained in cefathiamidine crude product has：It removes acetyl cefathiamidine, remove acetyl oxygen cephalo
It is contained in the 7ACA that sulphur amidine, reaction raw materials residue acetyl bromide -7ACA, N, N '-di-isopropyl thioureas and production fermentation obtain
High-molecular compound derived from impurity.
Wherein, residual impurity acetyl bromide -7ACA is maximum to the safety effects of cefathiamidine.Have now been found that the god of people
Very sensitive to the compound of bromine through system, after injecting in human body or absorbing the compound of a small amount of bromine, nerve will be gradually numb
Numbness, mainly since bromide ion plays the role of that cerebral cortex movement, bromine-containing compound is inhibited to have different degrees of poison secondary human body
Effect.In addition, the 7ACA used in production is fermentation gained, has a small amount of high-molecular compound impurity and generate, to cause
Cephalosporin analog antibiotic can all be influenced by macromolecule impurity derivative, and such impurity can make human body generate allergic reaction,
Harm is very big.We are in the reaction and subtractive process for preparing cefathiamidine, if it is possible to control acetyl bromide -7ACA and macromolecule
The residual quantity of impurity effectively can reduce or remove its residual in cefathiamidine finished product, for promoting the peace of cefathiamidine
Full property is of great importance.
Version in 2005《Chinese Pharmacopoeia》Provide that single impurity highest content is no more than 1.0%, total impurities content is no more than
2.5%；Version in 2010《Chinese Pharmacopoeia》Provide that single impurity, highest content are no more than 0.5% total impurities content and are no more than 1.5%；Closely
2015 phases version《Chinese Pharmacopoeia》Revised edition provides that the highest content of acetyl bromide -7ACA is no more than 0.1%, other single miscellaneous highests contain
Amount is no more than 0.5%, and total impurities content is no more than 1.5%.The quality requirement of cefathiamidine substantially increases, it is desirable for preparing high-purity
Cefathiamidine product.In addition, there is cefathiamidine internal salt structure, case of thermal instability to be easy to happen during production storage
Degradation.And the raising of cefathiamidine purity, it is also beneficial to the raising of cefathiamidine stability.
Invention content
The present invention in order to solve it is existing prepare the technical problem that impurity residual quantity is high present in the technique of cefathiamidine, carry
For a kind of effective preparation method for reducing acetyl bromide -7ACA and the remaining cefathiamidine of macromolecule impurity.
The technical scheme is that a kind of technique preparing cefathiamidine, in acetyl bromide -7ACA and N, N '-diisopropyls
In the reaction of base thiocarbamide or after reaction, water is added（Or the inorganic salt solution of water）As secondary solvent.
, not only can be to avoid the generation of side reaction by strictly controlling the amount of secondary solvent, but also acetyl bromide -7ACA can be reduced
Residual, and reaction yield is high.After obtaining crude product, crude product is dissolved with pure water, reuses polarity or low polar solvent aqueous layer extracted,
Remove endogenous macromolecule impurity.
Implementation by the method for the invention just can effectively control acetyl bromide-during preparing cefathiamidine crude product
The residual quantity of 7ACA makes it be reduced to 0.2% or lower by original 1.0% or so in the residual quantity of cefathiamidine crude product, into one
In the cefathiamidine crystal that one-step refining obtains, the content of acetyl bromide -7ACA can be reduced to 0.1% or lower, greatly reduce it
Residual in cefathiamidine finished product.
According to the present invention, it is as follows that technology of the invention solves concrete scheme：
Scheme 1：Acetyl bromide -7ACA, reaction dissolvent and cosolvent water are added into reactor（Or aqueous solution）, alkali, which is added, to be made
Acetyl bromide -7ACA is completely dissolved, and N, N '-di-isopropyl thioureas, heating reaction, after reaction stirring cooling, drop is then added
Add crystallization solvent, cefathiamidine crude product is obtained after suction filtration.
Scheme 2：Acetyl bromide -7ACA, reaction dissolvent and alkali are added into reactor makes acetyl bromide -7ACA be completely dissolved, so
After be added N, N '-di-isopropyl thioureas, heating reaction after reaction, adds cosolvent water（Or aqueous solution）Stirring cooling,
Crystallization solvent is added dropwise, cefathiamidine crude product is obtained after suction filtration.
After obtained crude product is dissolved with pure water, it is added that organic solvent aqueous layer extracted is primary, and obtained aqueous solution is with dilute
Acid for adjusting pH=2.5~6 are subsequently cooled to 0~5 DEG C, and acetone crystallization is added dropwise.It filters, washing, be dried in vacuo to get to high-purity
Cefathiamidine.
Its reaction equation is as follows：
Wherein, the dosage of acetyl bromide -7ACA and N, N '-di-isopropyl thiourea is 1 in molar ratio:1~1.5, preferably 1:1~
1.2。
The reaction dissolvent is dichloromethane, chloroform, dichloroethanes, N,N-dimethylformamide, N, N- dimethylacetamides
Amine, dimethyl sulfoxide (DMSO), tetrahydrofuran, 1,2- dioxane, methanol, ethyl alcohol, isopropanol, ethyl acetate, methyl acetate, acetic acid are different
The dosage of the one or two of propyl ester, n-hexane and hexamethylene, the preferred dichloromethane of reaction dissolvent or dichloroethanes, solvent is 1
~20mL/g acetyl bromides -7ACA.
The alkali is organic bases and sodium carbonate, sodium bicarbonate, potassium carbonate, the carbonic acid such as triethylamine, diethylamine or ammonium hydroxide
Organic bases, mole usage amount such as the inorganic bases such as caesium, preferably triethylamine, diethylamine or ammonium hydroxide are the 0.1~3 of acetyl bromide -7ACA
Times.
The secondary solvent is the aqueous solutions such as sodium chloride, calcium chloride, magnesium chloride, ammonium chloride, the ammonium sulfate of water and water, preferably
Water, dosage are 0.1~1mL/g acetyl bromides -7ACA.
Preferably 30~40 DEG C of the reaction temperature, preferably 1~4h the time required to reaction.
The extractant is esters solvents, dichloromethane, two chloroethenes such as ethyl acetate, methyl acetate, isopropyl acetate
One or more solvents such as alkane, ether, methyl tertiary butyl ether(MTBE), toluene, acetone, tetrahydrofuran, methanol, ethyl alcohol, isopropanol.It is preferred that
The esters solvents such as ethyl acetate, methyl acetate, isopropyl acetate, dosage volume are 10~100 times of secondary solvent.
The diluted acid be dilute hydrochloric acid, dilute sulfuric acid, phosphoric acid,diluted, dust technology and acetic acid, formic acid, methanesulfonic acid, citric acid, to toluene
The dilute mineral acids such as the aqueous solutions of organic acids such as sulfonic acid, preferably dilute hydrochloric acid, dust technology, dilute sulfuric acid, phosphoric acid,diluted.
The crystallization solvent is dichloromethane, acetone, methanol, ethyl alcohol, isopropanol, ether, methyl tertiary butyl ether(MTBE), tetrahydrochysene furan
Mutter, be one or two kinds of in n,N-Dimethylformamide, petroleum ether, n-hexane and hexamethylene, preferably dichloromethane, acetone, methanol,
One or both of ethyl alcohol, isopropanol, crystallization solvent dosage are 1~20mL/g acetyl bromides -7ACA.
Compared with prior art, the present invention passes through in acetyl bromide -7ACA and N, the reaction of N '-di-isopropyl thioureas or anti-
Ying Hou adds a small amount of water（Or the inorganic salt solution of water）As secondary solvent, the stringent amount for controlling secondary solvent can both be kept away
Exempt from the generation of side reaction, and the residual of acetyl bromide -7ACA can be reduced, and reaction yield is high.After obtaining crude product, dissolved with pure water
Crude product reuses polarity or low polar solvent aqueous layer extracted, removes endogenous macromolecule impurity.Acetyl bromide -7ACA and macromolecule
The content of derivative impurity can be reduced to 0.1% or less even lower, and other impurities can be reduced to 0.2% or less even more
It is low, meet control requirement of the newest pharmacopeia in relation to substance.Operation is simple by the present invention, yield is high, impurity content can be with
It reduces very much, is conducive to be refining to obtain high-purity cefathiamidine product, is suitable for industrialized production.
Description of the drawings
Fig. 1 is the sample detection collection of illustrative plates of comparative test example 1
Fig. 2 is the testing result of comparative test example 1
Fig. 3 is the sample detection collection of illustrative plates of embodiment 2
Fig. 4 is the inspection result of embodiment 2
Fig. 5 is the nuclear-magnetism test map of embodiment 2.
Specific embodiment
Comparative test example 1：
DCM is sequentially added in the reaction bulb of 1L（Dichloromethane）400 mL、TEA（Triethylamine）20 mL, acetyl bromide-
7ACA 50g stir dissolved clarification, add N, 22.5 g of N- di-isopropyl thioureas, and after stirring dissolved clarification, heating reaction solution extremely returns
Stream after reacting 2-3 hours, stops reacting, warm to 10 DEG C~15 DEG C in drop.Acetone 200mL is added dropwise, stirring and crystallizing is added dropwise
Afterwards, it in 8~12 DEG C of insulated and stirreds, filters, 100mL acetone rinsing filter cakes are drained and then be added to filter cake, after draining, will filter
Cake is added in the reaction bulb of 1L, and 60~100mL of pure water is then added and stirs dissolved clarification, adds 1 g of activated carbon, is stirred at room temperature
30min is filled into crystallization reaction bottle, and pH value of solution=5.0 are adjusted with dilute hydrochloric acid, and obtained clarification mixed liquor is cooled to 0~5 DEG C,
600~1000mL of acetone is added dropwise, after completion of dropwise addition, in 0~5 DEG C of insulated and stirred 30min, filters, after filter cake is drained, uses
100mL acetone rinsing filter cakes.After filter cake is drained, obtained product is put in vacuum drying chamber, vacuum drying is for 24 hours.It repeats
Purification operations twice, obtain off-white powder shape solid 31g, total recovery 51.7%.The quality for obtaining highly finished product be it is single it is miscellaneous≤
0.5%, it is total it is miscellaneous≤1.5%, moisture≤1.0%.Acetyl bromide -7ACA 0.13% and high-molecular compound are miscellaneous it can be seen from Fig. 1,2
Matter 0.2~0.5%.
Embodiment 2:
In the reaction kettle of 10L, 5320 g of DCM are sequentially added（4L）、TEA （200mL）, acetyl bromide -7ACA 500g, stir
Dissolved clarification is mixed, cosolvent pure water 50mL is added, adds N, 225 g of N- di-isopropyl thioureas, after stirring dissolved clarification, heating reaction
Liquid is to reflux, after reacting 2-3 hours, stops reaction, drops interior warm to 0 DEG C~15 DEG C.Acetone 2L is added dropwise, stirring and crystallizing drips
Bi Hou is filtered, 1L acetone rinsing filter cakes are drained and then be added to filter cake, after draining, by filter cake in 8~12 DEG C of insulated and stirreds
It is added in the reaction kettle of 10L, pure water 600mL is then added and stirs dissolved clarification, adds 1080 g（1.2L）Ethyl acetate,
It stirring ten minutes, extracting impurities, after stratification, water layer is filled into crystallization reactor, and pH value of solution=5.0 are adjusted with dilute hydrochloric acid,
Obtained clarification mixed liquor is cooled to 0~5 DEG C, and acetone 5.6L is added dropwise, and after completion of dropwise addition, in 0~5 DEG C of insulated and stirred 30min, takes out
Filter, after filter cake is drained, with 400mL acetone rinsing filter cakes.After filter cake is drained, obtained product is put in vacuum drying chamber
Interior, vacuum drying is for 24 hours.Obtain 422 g of off-white powder shape solid, total recovery 70%.The quality for obtaining highly finished product be it is single it is miscellaneous≤
0.2%, it is total it is miscellaneous≤1.0%, moisture≤1.0%.Acetyl bromide -7ACA≤0.05% and high-molecular compound it can be seen from Fig. 3,4,5
The residual of impurity almost without.
Embodiment 3:
400 18 mL of mL, TEA of DCM, acetyl bromide -7ACA 50g are sequentially added in the reaction bulb of 1L, are stirred dissolved clarification, are added
Enter cosolvent pure water 10mL, adds N, 22.5 g of N- di-isopropyl thioureas, after stirring dissolved clarification, heating reaction solution to reflux,
After reaction 2-3 hours, stop reaction, cosolvent pure water 10mL is added, temperature is to 10 DEG C~15 DEG C in drop.Acetone 200mL is added dropwise, stirs
Crystallization is mixed, after being added dropwise, in 8~12 DEG C of insulated and stirreds, is filtered, the filter of 100mL acetone rinsings is drained and then be added to filter cake
After draining, filter cake is added in the reaction bulb of 1L for cake, and pure water 60mL is then added and stirs dissolved clarification, adds 108 g
（120 mL）Ethyl acetate, stir ten minutes, extracting impurities, after stratification, water layer is filled into crystallization reaction bottle, and use is dilute
Hydrochloric acid conditioning solution pH=4.5, obtained clarification mixed liquor are cooled to 0~5 DEG C, acetone 560mL are added dropwise, after completion of dropwise addition, in 0
~5 DEG C of insulated and stirred 30min are filtered, after filter cake is drained, with 100mL acetone rinsing filter cakes.After filter cake is drained, it will obtain
Product be put in vacuum drying chamber, vacuum drying for 24 hours.Obtain off-white powder shape solid 37g, total recovery 61.7%.Obtain essence
The quality of product be it is single it is miscellaneous≤0.2%, it is total it is miscellaneous≤1.0%, moisture≤1.0%.Acetyl bromide -7ACA≤0.05% and high-molecular compound
The residual of impurity almost without.
Embodiment 4:
400 20 mL of mL, TEA of DCM, acetyl bromide -7ACA 50g are sequentially added in the reaction bulb of 1L, stir dissolved clarification, then
Addition N, 22.5 g of N- di-isopropyl thioureas, after stirring dissolved clarification, heating reaction solution after reacting 2-3 hours, stops to flowing back
Reaction drops interior temperature to 10 DEG C~15 DEG C.It is added dropwise acetone 200mL, stirring and crystallizing, after being added dropwise, in 8~12 DEG C of insulated and stirreds,
It filtering, filter cake is drained and then is added 100mL acetone rinsing filter cakes, after draining, filter cake is added in the reaction bulb of 1L,
Then pure water 60mL is added and stirs dissolved clarification, adds 108 g（120 mL）Ethyl acetate, stir ten minutes, extracting impurities,
After stratification, water layer is filled into crystallization reaction bottle, and pH value of solution=5.0 are adjusted with dilute hydrochloric acid, obtained clarification mixed liquor cooling
To 0~5 DEG C, acetone 560mL is added dropwise, after completion of dropwise addition, in 0~5 DEG C of insulated and stirred 30min, filters, after filter cake is drained, uses
100mL acetone rinsing filter cakes.After filter cake is drained, obtained product is put in vacuum drying chamber, vacuum drying is for 24 hours.It obtains
Off-white powder shape solid 37g, total recovery 61.7%.The quality for obtaining highly finished product be it is single it is miscellaneous≤0.2%, it is total it is miscellaneous≤1.0%, moisture
≤1.0%.The residual of acetyl bromide -7ACA 0.09% and high-molecular compound impurity almost without.
Embodiment 5
Acetyl bromide -7ACA, reaction dissolvent and cosolvent water are added into reactor（Or aqueous solution）, alkali, which is added, makes bromine second
Acyl -7ACA is completely dissolved, and N, N '-di-isopropyl thioureas, heating reaction, after reaction stirring cooling, dropwise addition analysis is then added
Brilliant solvent obtains cefathiamidine crude product after suction filtration.
After obtained crude product is dissolved with pure water, it is added that organic solvent aqueous layer extracted is primary, and obtained aqueous solution is with dilute
Acid for adjusting pH=2.5~6 are subsequently cooled to 0~5 DEG C, and acetone crystallization is added dropwise.It filters, washing, be dried in vacuo to get to high-purity
Cefathiamidine.
Wherein, the dosage of acetyl bromide -7ACA and N, N '-di-isopropyl thiourea is 1 in molar ratio:1~1.5, preferably 1:1~
1.2。
The reaction dissolvent is dichloromethane, chloroform, dichloroethanes, N,N-dimethylformamide, N, N- dimethylacetamides
Amine, dimethyl sulfoxide (DMSO), tetrahydrofuran, 1,2- dioxane, methanol, ethyl alcohol, isopropanol, ethyl acetate, methyl acetate, acetic acid are different
The dosage of the one or two of propyl ester, n-hexane and hexamethylene, solvent is 1~20mL/g acetyl bromides -7ACA.
The alkali is organic bases and sodium carbonate, sodium bicarbonate, potassium carbonate, the carbonic acid such as triethylamine, diethylamine or ammonium hydroxide
The inorganic bases such as caesium, mole usage amount are 0.1~3 times of acetyl bromide -7ACA.
The water such as the secondary solvent is water and aqueous solution is water sodium chloride, calcium chloride, magnesium chloride, ammonium chloride, ammonium sulfate
Solution, dosage are 0.1~1mL/g acetyl bromides -7ACA.
Preferably 30~40 DEG C of the reaction temperature, preferably 1~4h the time required to reaction.
The extractant is esters solvents, dichloromethane, two chloroethenes such as ethyl acetate, methyl acetate, isopropyl acetate
One or more solvents such as alkane, ether, methyl tertiary butyl ether(MTBE), toluene, acetone, tetrahydrofuran, methanol, ethyl alcohol, isopropanol.Dosage
Volume is 10~100 times of secondary solvent.
The diluted acid be dilute hydrochloric acid, dilute sulfuric acid, phosphoric acid,diluted, dust technology and acetic acid, formic acid, methanesulfonic acid, citric acid, to toluene
The aqueous solutions of organic acids such as sulfonic acid.
The crystallization solvent is dichloromethane, acetone, methanol, ethyl alcohol, isopropanol, ether, methyl tertiary butyl ether(MTBE), tetrahydrochysene furan
It mutters, is one or two kinds of in n,N-Dimethylformamide, petroleum ether, n-hexane and hexamethylene, crystallization solvent dosage is 1~20mL/g
Acetyl bromide -7ACA.
Embodiment 6
Acetyl bromide -7ACA, reaction dissolvent and alkali are added into reactor makes acetyl bromide -7ACA be completely dissolved, and is then added
N, N '-di-isopropyl thiourea, heating reaction, after reaction, add cosolvent water（Or aqueous solution）Stirring cooling, is added dropwise analysis
Brilliant solvent obtains cefathiamidine crude product after suction filtration.
After obtained crude product is dissolved with pure water, it is added that organic solvent aqueous layer extracted is primary, and obtained aqueous solution is with dilute
Acid for adjusting pH=2.5~6 are subsequently cooled to 0~5 DEG C, and acetone crystallization is added dropwise.It filters, washing, be dried in vacuo to get to high-purity
Cefathiamidine.
Wherein, the dosage of acetyl bromide -7ACA and N, N '-di-isopropyl thiourea is 1 in molar ratio:1~1.5, preferably 1:1~
1.2。
The reaction dissolvent is dichloromethane, chloroform, dichloroethanes, N,N-dimethylformamide, N, N- dimethylacetamides
Amine, dimethyl sulfoxide (DMSO), tetrahydrofuran, 1,2- dioxane, methanol, ethyl alcohol, isopropanol, ethyl acetate, methyl acetate, acetic acid are different
The dosage of the one or two of propyl ester, n-hexane and hexamethylene, solvent is 1~20mL/g acetyl bromides -7ACA.
The alkali is organic bases and sodium carbonate, sodium bicarbonate, potassium carbonate, the carbonic acid such as triethylamine, diethylamine or ammonium hydroxide
The inorganic bases such as caesium, mole usage amount are 0.1~3 times of acetyl bromide -7ACA.
The water such as the secondary solvent is water and aqueous solution is water sodium chloride, calcium chloride, magnesium chloride, ammonium chloride, ammonium sulfate
Solution, dosage are 0.1~1mL/g acetyl bromides -7ACA.
Preferably 30~40 DEG C of the reaction temperature, preferably 1~4h the time required to reaction.
The extractant is esters solvents, dichloromethane, two chloroethenes such as ethyl acetate, methyl acetate, isopropyl acetate
One or more solvents such as alkane, ether, methyl tertiary butyl ether(MTBE), toluene, acetone, tetrahydrofuran, methanol, ethyl alcohol, isopropanol.Dosage
Volume is 10~100 times of secondary solvent.
The diluted acid be dilute hydrochloric acid, dilute sulfuric acid, phosphoric acid,diluted, dust technology and acetic acid, formic acid, methanesulfonic acid, citric acid, to toluene
The aqueous solutions of organic acids such as sulfonic acid.
The crystallization solvent is dichloromethane, acetone, methanol, ethyl alcohol, isopropanol, ether, methyl tertiary butyl ether(MTBE), tetrahydrochysene furan
It mutters, is one or two kinds of in n,N-Dimethylformamide, petroleum ether, n-hexane and hexamethylene, crystallization solvent dosage is 1~20mL/g
Acetyl bromide -7ACA.
Claims (1)
1. a kind of technique preparing cefathiamidine, it is characterized in that synthetic route is as follows：
Preparation method is：Water is added in acetyl bromide -7ACA and N, the reaction of N '-di-isopropyl thioureas as secondary solvent；Tool
Body scheme is：Acetyl bromide -7ACA, dichloromethane and secondary solvent water are added into reactor, triethylamine, which is added, makes system dissolved clarification
Afterwards, N, N '-di-isopropyl thioureas are added, heating reaction, after reaction, cooling, dropwise addition crystallization solvent acetone, suction filtration obtain
Cefathiamidine crude product；After obtained cefathiamidine crude product is dissolved with pure water, addition ethyl acetate aqueous layer extracted is primary, obtains
Aqueous solution adjusts pH=2.5~6 with dilute hydrochloric acid, and then cooling, dropwise addition crystallization solvent acetone is filtered, washed, after vacuum drying
Obtain high-purity cefathiamidine, the dosage of the acetyl bromide -7ACA and N, N- di-isopropyl thiourea is 1 in molar ratio:1~1.2；
The reaction temperature is 30~40 DEG C, is 1~4h the time required to reaction.
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| CN108948048B (en) * | 2018-07-26 | 2020-04-07 | 华北制药河北华民药业有限责任公司 | Refining method of cefathiamidine |
| CN113999253B (en) * | 2021-11-17 | 2023-01-24 | 国药集团威奇达药业有限公司 | Comprehensive recovery method of effective components in N-haloacetyl-7-ACA crystallization mother liquor |
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