CN109503630A - A kind of preparation method of Desacetylcefotaxime - Google Patents
A kind of preparation method of Desacetylcefotaxime Download PDFInfo
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- CN109503630A CN109503630A CN201811532899.6A CN201811532899A CN109503630A CN 109503630 A CN109503630 A CN 109503630A CN 201811532899 A CN201811532899 A CN 201811532899A CN 109503630 A CN109503630 A CN 109503630A
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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
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
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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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- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a kind of preparation method of Desacetylcefotaxime, using D-7-ACA and 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester as reaction raw materials, by carrying out match control to raw material proportioning, reaction temperature, system pH value, Desacetylcefotaxime finished product is made in this method.The present invention provides a kind of process for preparing Desacetylcefotaxime by chemically synthesized means, can high yield, high-purity, easily obtain Desacetylcefotaxime standard items, and then improve the production quality of Cefotaxime Sodium.
Description
Technical field
The present invention relates to organic synthesis field more particularly to the process of preparing of Desacetylcefotaxime.
Background technique
Cefotaxime Sodium ([6R- [6 Α, 7 Β (Z)]] -3- [(acetoxyl group) methyl] -7- [2- (2- amino -4- thiazole
Base) -2- (methoxyimino) acetamido] -8- oxo -5- thia -1- azabicyclic [4.2.0] -2- octene -2- carboxylic acid sodium)
Be third broad-spectrum cephalosporin class antibiotic, have powerful bactericidal activity to Glan negative bacterium and positive bacteria, to Escherichia coli,
Bacillus influenzae, pneumobacillus, proteus mirabilis, the antibacterial action of Salmonella are strong compared with cefoperazone；Commonly used in sensitive bacteria
The positions such as caused respiratory tract, the urinary tract, bone and joint, skin and soft tissue, abdominal cavity, biliary tract, alimentary canal, face, genitals
Infection；Infection caused by burn, wound and septicemia, maincenter are infected also effective.
Cefotaxime Sodium can degrade generate Desacetylcefotaxime during storage.Head containing Desacetylcefotaxime
Spore thiophene oxime sodium can reduce the stability of drug, curative effect,；Influence the quality and purity of product；So the life of Desacetylcefotaxime
At, it is always the important research field of Cefotaxime Sodium industrialized production and control of product quality, meanwhile, Desacetylcefotaxime
It is also the major impurity of the semi-synthetic cephalosporin medicament of the third generation, is one of the emphasis of cephalosporins medicine impurity research.Remove acetyl
Cefotaxime structural formula are as follows:
Currently, domestic do not find the document report that the impurity is prepared by the means of chemical synthesis and purifying also, meanwhile, it is external
The data of related synthesis is not found, but prepares Desacetylcefotaxime impurity Cefotaxime sodium drug quality control, especially yet
The impurity spectrum research work of its Cefotaxime sodium imitation medicine Conformance Assessment is essential.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of blank for filling up the prior art, provide a kind of by chemistry conjunction
At means prepare the process of Desacetylcefotaxime, so as to high yield, high-purity, easily obtain and remove acetyl
Cefotaxime standard items, and then improve the production quality of Cefotaxime Sodium.
In order to solve the above technical problems, the technical solution used in the present invention is as follows:
A kind of preparation method of Desacetylcefotaxime, this method is using D-7-ACA and 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester as reaction raw materials, by right
Raw material proportioning, reaction temperature, system pH value carry out match control, and Desacetylcefotaxime finished product is made；This method includes such as
Lower step:
A, the preparation of D-7-ACA solution:
Under the conditions of being not higher than 20 DEG C of temperature, chemical compounds I i.e. 10~20 parts by weight of D-7-ACA raw material are taken, it is dissolved into 100~
It in the compounding organic solvent of 300 parts by volume, stirs evenly, obtains D-7-ACA solution, it is spare；It is wrapped in the compounding organic solvent
Isopropanol and/or methanol and/or ethyl alcohol containing 10~50 parts by volume；
B, the preparation of Desacetylcefotaxime crude product:
Under the conditions of -10~10 DEG C of temperature, compound ii, that is, 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester 15 is added into step A acquired solution while stirring
~25 parts by weight continue to stir and be added 1.5~2.5 parts by weight of Sodium Metabisulfite, triethylamine 10~20 are then slowly added dropwise
Parts by volume, rate of addition are not more than 1mL/min, are added dropwise and continue to be stirred to react 2~5h, obtain containing Desacetylcefotaxime
The reaction solution of crude product；
C, the purification of Desacetylcefotaxime:
5~35 DEG C of C-1, temperature control, reaction solution purified water obtained by step B extract 2 times or more, every time 30~50 parts by volume, then
Liquid separation simultaneously collects, merges water phase, then is washed to remove impurity, so with the methylene chloride of 40~60 parts by volume to gained water phase
After discard methylene chloride；
Water phase obtained by C-2, upper step continues to carry out decolorization with active carbon, filtrate is filtered to take, then 0~5 DEG C of temperature control, to gained
The isopropanol of 50~70 parts by volume is added in filtrate, system pH is then adjusted to 1.0~4.0, stirs 15min or more, analysis
Crystalline substance is filtered, washed, dries to get compound III Desacetylcefotaxime crystal.
As a preferred technical solution of the present invention, the unit of the parts by weight is g or Kg, the unit of the parts by volume
Correspond to mL or L.
As a preferred technical solution of the present invention, in step A, the compounding organic solvent be methylene chloride, toluene,
Chloroform, dichloroethanes or combinations thereof object, while compounding addition isopropanol, methanol, ethyl alcohol or combinations thereof object.
As a preferred technical solution of the present invention, in step B, divide at least three batch into step A acquired solution plus
Enter compound ii i.e. 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester.
As a preferred technical solution of the present invention, in step C-2, acid that regulation system pH is used is dilute hydrochloric acid, dilute
The combination of one or more of inorganic acids such as sulfuric acid.
As a preferred technical solution of the present invention, in step C-2, filter cake is dry with 35~45 DEG C of baking oven decompressions after suction filtration
Dry 3~5h.
As a preferred technical solution of the present invention, this method is comprised the following steps:
A, the preparation of D-7-ACA solution: under the conditions of 10 DEG C of temperature, taking chemical compounds I i.e. 15 parts by weight of D-7-ACA raw material, molten
Solution is stirred evenly into the compounding organic solvent of 180 parts by volume, obtains D-7-ACA solution, spare；The compounding organic solvent
In isopropanol and/or methanol and/or ethyl alcohol comprising 30 parts by volume；
B, it the preparation of Desacetylcefotaxime crude product: under the conditions of 0 DEG C of temperature, is added while stirring into step A acquired solution
20 parts by weight of compound ii, that is, 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester continue to stir and be added 2 parts by weight of Sodium Metabisulfite, are then slowly added dropwise three
15 parts by volume of ethamine, rate of addition 0.8mL/min are added dropwise and continue to be stirred to react 3h, obtain containing removing acetyl cephalo thiophene
The reaction solution of oxime crude product；
C, the purification of Desacetylcefotaxime:
15 DEG C of C-1, temperature control, reaction solution purified water obtained by step B extract 3 times, every time 40 parts by volume, then liquid separation and collect,
Merge water phase, then gained water phase is washed to remove impurity with the methylene chloride of 50 parts by volume, then discards methylene chloride；
Water phase obtained by C-2, upper step continues to carry out decolorization with active carbon, filtrate is filtered to take, then 0~5 DEG C of temperature control, to gained
The isopropanol of 60 parts by volume is added in filtrate, system pH is then adjusted to 2.0~3.0, stirs 30min crystallization, filters, takes out
After filter 4h is dried under reduced pressure to get compound III Desacetylcefotaxime crystal for 40 DEG C of filter cake baking oven.
The beneficial effects of adopting the technical scheme are that synthetic operation of the invention is simple and fast, it is main to produce
Object is solid, easily separated purifying, does not need the operation such as chromatography.This is also an obvious and protrusion of technical solution of the present invention
Beneficial effect.
Include the technical solution controlled temperature of reaction system in the present invention, is recognized according to our research and development, it is low
The control of warm environment has materially affect for the synthesis of product, under the temperature control process that the present invention gropes, target product
Yield remain at 50% or more, reach as high as 52.36%.
PH value of the invention is precisely controlled and the consumption proportion of each material, acquisition and its purity table for product
Now have and significantly affects, under the specific soda acid control condition of present invention research and development determining material proportion and specific link, gained
The purity (HPLC) of product is not less than 99.2%, reaches as high as 99.66%.
In view of not having through chemically synthesized means the document report for preparing the impurity also both at home and abroad at present, in view of this hair
The Desacetylcefotaxime preparation method of bright offer can quick, easy, efficiently obtain the control of Desacetylcefotaxime impurity
Product, thus, technical solution of the present invention has weight for improving the quality of Cefotaxime Sodium and reducing the risk etc. of clinical application
The theory significance and practical application value wanted.
In application value, the present invention can high yield, high-purity, easily obtain Desacetylcefotaxime standard items,
And then improve the production quality of Cefotaxime Sodium.
Specific embodiment
The chemical process of synthesis technology of the present invention given below:
。
The present invention is described in detail in following embodiment.Various raw materials used in the present invention and items of equipment are conventional city
Product is sold, can be bought and be directly obtained by market.
Embodiment 1
15.14gD-7-ACA, 150mL methylene chloride, 30mL isopropanol, 5~10 DEG C of conditions of temperature control are added in the four-hole bottle of 250mL
Under, stirring is added 20.10gAE- active ester, continues to stir evenly, and 2g Sodium Metabisulfite is added, triethylamine is slowly added dropwise
15mL, about 20min are added dropwise, and are stirred to react 3h, and under conditions of 5~10 DEG C of temperature control, reaction solution purified water extracts 3 times, often
Secondary 40mL, liquid separation collect and merge water phase, then washed water phase 1 time with 50mL methylene chloride；Methylene chloride is discarded, water phase is in right amount
Active carbon decolourize, filter, 0~5 DEG C of temperature control, 60mL isopropanol, stirring is added in filtrate, then that 10% hydrochloric acid is slowly added dropwise is molten
System PH is adjusted to 1.0~2.0, stirs 30min, filtered by liquid, and 40 DEG C of filter cake baking oven are dried under reduced pressure 4h, and weighing is produced
Product 18.45g (yield 52.36%).The purity (HPLC) of target product obtained is 99.63% in the embodiment.
Embodiment 2
15.02gD-7-ACA, 150mL dichloroethanes, 30mL isopropanol, 0~5 DEG C of condition of temperature control are added in the four-hole bottle of 250mL
Under, stirring is added 20.08gAE- active ester, continues to stir evenly, and 2g Sodium Metabisulfite is added, triethylamine is slowly added dropwise
15mL, about 20min are added dropwise, and are stirred to react 3h, and under conditions of 10~15 DEG C of temperature control, reaction solution purified water extracts 3 times, often
Secondary 40mL, liquid separation collect and merge water phase, then washed water phase 1 time with 50mL dichloroethanes；Dichloroethanes is discarded, water phase is in right amount
Active carbon decolourize, filter, 0~5 DEG C of temperature control, 60mL isopropanol, stirring is added in filtrate, then that 10% hydrochloric acid is slowly added dropwise is molten
System PH is adjusted to 2.0~3.0, stirs 30min, filtered by liquid, and 40 DEG C of filter cake baking oven are dried under reduced pressure 4h, and weighing is produced
Product 18.36g (yield 52.31%).The purity (HPLC) of target product obtained is 99.49% in the embodiment.
Embodiment 3
15.08gD-7-ACA, 150mL methylene chloride, 30mL methanol, temperature control -5~0 DEG C condition are added in the four-hole bottle of 250mL
Under, stirring is added 20.01gAE- active ester, continues to stir evenly, and 2g Sodium Metabisulfite is added, triethylamine is slowly added dropwise
15mL, about 20min are added dropwise, and are stirred to react 3h, and under conditions of 10~15 DEG C of temperature control, reaction solution purified water extracts 3 times, often
Secondary 40mL, liquid separation collect and merge water phase, then washed water phase 1 time with 50mL methylene chloride；Methylene chloride is discarded, water phase is in right amount
Active carbon decolourize, filter, 0~5 DEG C of temperature control, 60mL methanol is added in filtrate, then 10% hydrochloric acid solution is slowly added dropwise in stirring,
System PH is adjusted to 3.0~4.0, stirs 30min, is filtered, 40 DEG C of filter cake baking oven are dried under reduced pressure 4h, and weighing obtains product
18.02g (yield 51.35%).The purity (HPLC) of target product obtained is 99.38% in the embodiment.
Embodiment 4
7.58gD-7-ACA, 75mL methylene chloride, 15mL isopropanol, temperature control -10~-5 DEG C condition are added in the four-hole bottle of 250mL
Under, stirring is added 10.00gAE- active ester, continues to stir evenly, and 1g Sodium Metabisulfite is added, triethylamine is slowly added dropwise
7.5mL, about 10min are added dropwise, and are stirred to react 2h, and under conditions of 20~25 DEG C of temperature control, reaction solution is extracted 3 times with purified water,
Each 20mL, liquid separation collect and merge water phase, then washed water phase 1 time with 30mL methylene chloride；Methylene chloride is discarded, water phase is used suitable
The active carbon of amount decolourizes, filtering, and 0~5 DEG C of temperature control, 30mL isopropanol, stirring is added in filtrate, then 10% hydrochloric acid is slowly added dropwise
System PH is adjusted to 2.0~3.0, stirs 30min, filtered, 40 DEG C of filter cake baking oven are dried under reduced pressure 4h, and weighing obtains by solution
Product 8.98g (yield 51.08%).The purity (HPLC) of target product obtained is 99.24% in the embodiment.
Embodiment 5
It is added 15.27gD-7-ACA in the four-hole bottle of 250mL, 150mL methylene chloride, 30mL ethyl alcohol, under the conditions of 0~5 DEG C of temperature control,
Stirring is added 20.07gAE- active ester, continues to stir evenly, and 2g Sodium Metabisulfite is added, triethylamine 15mL is slowly added dropwise,
About 20min is added dropwise, and is stirred to react 3h, and under conditions of 10~15 DEG C of temperature control, reaction solution purified water extracts 3 times, every time
40mL, liquid separation collect and merge water phase, then washed water phase 1 time with 50mL methylene chloride；Discard methylene chloride, water phase is with suitable
Active carbon decolourizes, filtering, and 0~5 DEG C of temperature control, 60mL ethyl alcohol, stirring is added in filtrate, then 10% hydrochloric acid solution is slowly added dropwise, will
System PH is adjusted to 2.0~3.0, stirs 30min, filters, and 40 DEG C of filter cake baking oven are dried under reduced pressure 4h, and weighing obtains product
18.15g (yield 51.36%).The purity (HPLC) of target product obtained is 99.41% in the embodiment.
Embodiment 6
It is added 15.66gD-7-ACA in the four-hole bottle of 250mL, 150mL methylene chloride, 30mL ethyl alcohol, under the conditions of 0~5 DEG C of temperature control,
Stirring is added 20.13gAE- active ester, continues to stir evenly, and 2g Sodium Metabisulfite is added, triethylamine 15mL is slowly added dropwise,
About 20min is added dropwise, and is stirred to react 3h, and under conditions of 25~35 DEG C of temperature control, reaction solution purified water extracts 3 times, every time
40mL, liquid separation collect and merge water phase, then washed water phase 1 time with 50mL methylene chloride；Discard methylene chloride, water phase is with suitable
Active carbon decolourizes, filtering, and 0~5 DEG C of temperature control, 60mL ethyl alcohol, stirring is added in filtrate, then 10% sulfuric acid solution is slowly added dropwise, will
System PH is adjusted to 2.0~3.0, stirs 30min, filters, and 40 DEG C of filter cake baking oven are dried under reduced pressure 4h, and weighing obtains product
18.27g (yield 51.05%).The purity (HPLC) of target product obtained is 99.66% in the embodiment.
Embodiment 7
15.34gD-7-ACA, 150mL methylene chloride, 30mL ethyl alcohol, temperature control -5~0 DEG C condition are added in the four-hole bottle of 250mL
Under, stirring is added 20.20gAE- active ester, continues to stir evenly, and 2g Sodium Metabisulfite is added, triethylamine is slowly added dropwise
15mL, about 20min are added dropwise, and are stirred to react 3h, and under conditions of 15~25 DEG C of temperature control, reaction solution purified water extracts 3 times, often
Secondary 40mL, liquid separation collect and merge water phase, then washed water phase 1 time with 50mL methylene chloride；Methylene chloride is discarded, water phase is in right amount
Active carbon decolourize, filter, 0~5 DEG C of temperature control, 60mL ethyl alcohol is added in filtrate, then 10% acetic acid solution is slowly added dropwise in stirring,
System PH is adjusted to 2.0~3.0, stirs 30min, is filtered, 40 DEG C of filter cake baking oven are dried under reduced pressure 4h, and weighing obtains product
18.33g (yield 51.58%).The purity (HPLC) of target product obtained is 99.52% in the embodiment.
Foregoing description is only proposed as the enforceable technical solution of the present invention, not as to the single of its technical solution itself
Restrictive condition.
Claims (7)
1. a kind of preparation method of Desacetylcefotaxime, it is characterised in that: this method is anti-with D-7-ACA and 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester
Raw material is answered, by carrying out match control to raw material proportioning, reaction temperature, system pH value, Desacetylcefotaxime finished product is made；
This method comprises the following steps:
A, the preparation of D-7-ACA solution:
Under the conditions of being not higher than 20 DEG C of temperature, chemical compounds I i.e. 10~20 parts by weight of D-7-ACA raw material are taken, it is dissolved into 100~
It in the compounding organic solvent of 300 parts by volume, stirs evenly, obtains D-7-ACA solution, it is spare；It is wrapped in the compounding organic solvent
Isopropanol and/or methanol and/or ethyl alcohol containing 10~50 parts by volume；
B, the preparation of Desacetylcefotaxime crude product:
Under the conditions of -10~10 DEG C of temperature, compound ii, that is, 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester 15 is added into step A acquired solution while stirring
~25 parts by weight continue to stir and be added 1.5~2.5 parts by weight of Sodium Metabisulfite, triethylamine 10~20 are then slowly added dropwise
Parts by volume, rate of addition are not more than 1mL/min, are added dropwise and continue to be stirred to react 2~5h, obtain containing Desacetylcefotaxime
The reaction solution of crude product；
C, the purification of Desacetylcefotaxime:
5~35 DEG C of C-1, temperature control, reaction solution purified water obtained by step B extract 2 times or more, every time 30~50 parts by volume, then
Liquid separation simultaneously collects, merges water phase, then is washed to remove impurity, so with the methylene chloride of 40~60 parts by volume to gained water phase
After discard methylene chloride；
Water phase obtained by C-2, upper step continues to carry out decolorization with active carbon, filtrate is filtered to take, then 0~5 DEG C of temperature control, to gained
The isopropanol of 50~70 parts by volume is added in filtrate, system pH is then adjusted to 1.0~4.0, stirs 15min or more, analysis
Crystalline substance is filtered, washed, dries to get compound III Desacetylcefotaxime crystal.
2. a kind of preparation method of Desacetylcefotaxime according to claim 1, it is characterised in that: the parts by weight
Unit is g or Kg, and the unit of the parts by volume corresponds to mL or L.
3. a kind of preparation method of Desacetylcefotaxime according to claim 1, it is characterised in that: described in step A
Compounding organic solvent be methylene chloride, toluene, chloroform, dichloroethanes or combinations thereof object, while compound addition isopropanol, methanol,
Ethyl alcohol or combinations thereof object.
4. a kind of preparation method of Desacetylcefotaxime according to claim 1, it is characterised in that: in step B, divide extremely
Compound ii, that is, 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester is added into step A acquired solution for few 3 batches.
5. a kind of preparation method of Desacetylcefotaxime according to claim 1, it is characterised in that: in step C-2, adjust
The acid that section system pH is used is the combination of one or more of inorganic acids such as dilute hydrochloric acid, dilute sulfuric acid.
6. a kind of preparation method of Desacetylcefotaxime according to claim 1, it is characterised in that: in step C-2, take out
3~5h is dried under reduced pressure for 35~45 DEG C of filter cake baking oven after filter.
7. a kind of preparation method of Desacetylcefotaxime according to claim 1, it is characterised in that: this method includes such as
Lower step:
A, the preparation of D-7-ACA solution: under the conditions of 10 DEG C of temperature, taking chemical compounds I i.e. 15 parts by weight of D-7-ACA raw material, molten
Solution is stirred evenly into the compounding organic solvent of 180 parts by volume, obtains D-7-ACA solution, spare；The compounding organic solvent
In isopropanol and/or methanol and/or ethyl alcohol comprising 30 parts by volume；
B, it the preparation of Desacetylcefotaxime crude product: under the conditions of 0 DEG C of temperature, is added while stirring into step A acquired solution
20 parts by weight of compound ii, that is, 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester continue to stir and be added 2 parts by weight of Sodium Metabisulfite, are then slowly added dropwise three
15 parts by volume of ethamine, rate of addition 0.8mL/min are added dropwise and continue to be stirred to react 3h, obtain containing removing acetyl cephalo thiophene
The reaction solution of oxime crude product；
C, the purification of Desacetylcefotaxime:
15 DEG C of C-1, temperature control, reaction solution purified water obtained by step B extract 3 times, every time 40 parts by volume, then liquid separation and collect,
Merge water phase, then gained water phase is washed to remove impurity with the methylene chloride of 50 parts by volume, then discards methylene chloride；
Water phase obtained by C-2, upper step continues to carry out decolorization with active carbon, filtrate is filtered to take, then 0~5 DEG C of temperature control, to gained
The isopropanol of 60 parts by volume is added in filtrate, system pH is then adjusted to 2.0~3.0, stirs 30min crystallization, filters, takes out
After filter 4h is dried under reduced pressure to get compound III Desacetylcefotaxime crystal for 40 DEG C of filter cake baking oven.
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| CN112458141A (en) * | 2020-11-06 | 2021-03-09 | 河北合佳创新医药科技有限公司 | Preparation method of 3-hydroxymethyl cefotaxime |
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