CN109293679A - A kind of preparation method of Cefazolin acetoxyl group analog - Google Patents
A kind of preparation method of Cefazolin acetoxyl group analog Download PDFInfo
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- CN109293679A CN109293679A CN201811325839.7A CN201811325839A CN109293679A CN 109293679 A CN109293679 A CN 109293679A CN 201811325839 A CN201811325839 A CN 201811325839A CN 109293679 A CN109293679 A CN 109293679A
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- cefazolin
- acetoxyl group
- group analog
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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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- 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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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a kind of preparation methods of Cefazolin acetoxyl group analog, using 7-ACA solution and tetrazoleacetic acid mixed anhydride solution as reaction raw materials, by carrying out match control to raw material proportioning, reaction temperature, system pH value, Cefazolin acetoxyl group analog finished product is made.The present invention provides a kind of process for preparing Cefazolin acetoxyl group analog by chemically synthesized means, it can stablize, efficiently obtain Cefazolin acetoxyl group analog standard items, and then improve the production quality of Cefazolin sodium.
Description
Technical field
The present invention relates to organic synthesis field more particularly to the process of preparing of Cefazolin acetoxyl group analog.
Background technique
Cefazolin sodium, chemical name are (6R, 7R) -3- [[(5- methyl-1,3,4- thiadiazoles -2- bases) sulphur] methyl] -
7- [(1H-TETRAZOLE -1- base) acetylamino] -8- oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- sodium formate.Head
Spore azoles woods sodium is first generation cephalosporin, has a broad antifungal spectrum, suitable for treating tympanitis caused by sensitive bacterial, bronchitis, lung
The respiratory tract infection such as inflammation, urinary tract infections, skin soft-tissue infection, bone joint infection, septicemia, infectious endocarditis, liver and gallbladder
The infection such as system infections and Eye Ear Nose And Throat section；Also it can be used as preoperative prophylactic.
In the production process of Cefazolin sodium, raw material 7-ACA is reacted with tetrazoleacetic acid can generate this impurity.Cephalo
Azoles woods acetoxyl group analog is also the important impurity of cephalosporins medicine.Cefazolin acetoxyl group analog structural formula:
Currently, domestic do not find the document report for preparing the impurity by chemically synthesized means also.However, just at present
Industry for, in order to improve Cefazolin sodium quality, reduce clinical application risk for, develop a kind of acquisition head
The method of spore azoles woods acetoxyl group analog standard items is very necessary and critical again.
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 Cefazolin acetoxyl group analog, so as to stablize, efficient obtain cephalo azoles
Woods acetoxyl group analog standard items, and then improve the production quality of Cefazolin 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 Cefazolin acetoxyl group analog, with 7-ACA solution and tetrazoleacetic acid mixed anhydride solution
Cefazolin acetyl oxygen is made by carrying out match control to raw material proportioning, reaction temperature, system pH value for reaction raw materials
Base analog finished product；This method comprises the following steps:
A, the preparation of 7-ACA solution: under the conditions of being not more than -5 DEG C of temperature, the i.e. 7-ACA dissolution of raw material of chemical compounds I is taken to arrive
In organic solvent, tetramethylguanidine is then slowly added dropwise thereto again, until 7-ACA dissolution completely, obtains 7-ACA solution,
It is spare；
B, under the conditions of being not more than -5 DEG C of temperature, compound ii i.e. four nitrogen the preparation of tetrazoleacetic acid mixed anhydride solution: are taken
Zole acetic acid is dissolved into organic solvent, and n,N-dimethylacetamide, triethylamine and pivaloyl chloride are then added thereto, obtains four
Methylguanidine mixed anhydride solution, it is spare；
C, 7-ACA solution obtained by step A C-1, the synthesis of Cefazolin acetoxyl group analog: is added drop-wise to step B institute
In tetrazoleacetic acid mixed anhydride solution, be stirred to react, then plus water-extraction and collect water phase；C-2, with alkali will obtained by upper step it is molten
The pH of liquid is adjusted to 6.0~10.5, and reaction is hydrolyzed；Hydrolyzate is collected after C-3, hydrolysis and carries out decolorization, then
PH value of solution is adjusted to 1.5~2.5 with acid, filters to obtain Primary product；Primary product obtained by C-4, upper step is stirred molten with organic solvent
It dissipates, using filter-washing-drying, obtains compound III, i.e. Cefazolin acetoxyl group analog finished product.
As a preferred technical solution of the present invention, this method further includes following steps: D, to cephalo azoles obtained by step C
Woods acetoxyl group analog is purified: D-1, the crude product of Cefazolin acetoxyl group analog obtained by step C is added to the water,
Then addition strong base-weak acid salt is complete to dissolving；D-2, using inorganic acid by upper step acquired solution adjust pH be 1.5~2.5, analysis
Solid out, filtering-washing-drying obtain Cefazolin acetoxyl group analog sterling.
As a preferred technical solution of the present invention, in step A, -5 DEG C~-25 DEG C of operating process temperature control, operation is completed
Afterwards in -30 DEG C or less preservation solution for standby；
As a preferred technical solution of the present invention, in step B, -10 DEG C~-30 DEG C of operating process temperature control, operate
In -30 DEG C or less preservation solution for standby after；
As a preferred technical solution of the present invention, in step C, -30 DEG C of initial temperature control hereinafter, plus temperature control 10 before water~
35 DEG C, 10~20 DEG C of temperature control after decolorization, 0~5 DEG C of temperature control after pH value of solution is adjusted to 1.5~2.5, after the reaction was completed, filter cake exists
Finished product is dried under reduced pressure to obtain at 30~50 DEG C.
As a preferred technical solution of the present invention, in step A, the 7-ACA, organic solvent, tetramethylguanidine three
Usage ratio are as follows: 20g:(100~200mL): (4~16mL)；In step B, in the tetrazoleacetic acid, organic solvent, N,
N- dimethyl acetamide, triethylamine, pivaloyl chloride usage ratio be 23.5g:(100~200mL): (30~50mL): (4~
16mL): (4~16mL).
As a preferred technical solution of the present invention, in step A, the 7-ACA, organic solvent, tetramethylguanidine three
Usage ratio are as follows: 20g:150mL:10mL；In step B, in the tetrazoleacetic acid, organic solvent, N, N- dimethylacetamide
Amine, triethylamine, pivaloyl chloride usage ratio be 23.5g:150mL:40mL:11mL:11mL.
As a preferred technical solution of the present invention, the usage ratio of organic solvent is 1 in step A and step B:
(0.8-1.2)v/v。
As a preferred technical solution of the present invention, in step A and step B, the organic solvent is methylene chloride, first
One of benzene, dichloroethanes or multiple combinations.
As a preferred technical solution of the present invention, in step C, adjust alkali used in pH be sodium carbonate, sodium bicarbonate,
The combination of one or more of triethylamine；Acid used in pH is adjusted as the combination of one or more of hydrochloric acid, sulfuric acid.
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 53% or more, highest is more than 60%.
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%, highest nearly 99.5%.
To sum up, it in view of not having through chemically synthesized means the document report for preparing the impurity also both at home and abroad at present, reflects
In Cefazolin acetoxyl group method for preparing analogue provided by the invention can quickly, it is easy, efficiently obtain Cefazolin
Acetoxyl group analog impurity reference substance, thus, quality and reduction of the technical solution of the present invention for raising Cefazolin sodium
The risk etc. of clinical application, has important theoretical significance and practical application value.
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
20.05g7-ACA is added in the four-hole bottle of 500mL, 150mL methylene chloride is stirred to react 15min, and temperature control is to -5 DEG C
~-10 DEG C, tetramethylguanidine 9.8mL is added dropwise, about 15min is added dropwise, continues to stir 30min, until 7-ACA all dissolves, cooling -
30 DEG C spare；150mL methylene chloride, 23.52g tetrazoleacetic acid, 40.2mLN, N- bis- are added in the four-hole bottle of another 500mL
Methylacetamide, stirs 15min by -10 DEG C~-15 DEG C of temperature control, and 10mL triethylamine is added dropwise with about 20min, finishes stirring 15min,
10mL pivaloyl chloride is added dropwise with about 30min, stirs 2h；< -30 DEG C of temperature control, 7-ACA lysate is added dropwise to tetrazoleacetic acid and is mixed
In acid anhydride, it is stirred to react 1h, then 10~35 DEG C of temperature control, 200mL water is added, adjusts pH6.0~6.5, stirring hydrolysis with triethylamine
15min collects water phase, and with active carbon decoloring, filtering is added 10% hydrochloric acid and adjusts pH to 1.5~2.5, then by system temperature
It is down to 0~5 DEG C of stirring 30min, is filtered, is leached filter cake with methylene chloride 100mL, refilter, filter cake is dry with 40 DEG C of baking oven decompressions
Dry 4h, weighing obtain product 25.31g.The yield for the target product made in the embodiment is that 58.09%, HPLC purity is
99.13%.
Gained Cefazolin acetoxyl group analog is further purified: the first step, and Cefazolin acetoxyl group is similar
The crude product of object is added to the water, and then adjusts pH to being completely dissolved.PH adjusting agent can be sodium carbonate, sodium bicarbonate, potassium carbonate, carbon
The strong base-weak acid salts such as potassium hydrogen phthalate.Second step, it is 1.0~3.0 that the solution that the first step is obtained, which adjusts pH, and solid is precipitated, filters, wash
Wash, dry to get finished product --- Cefazolin acetoxyl group analog.PH adjusting agent can be dilute hydrochloric acid, dilute sulphur in this step
The inorganic acids such as acid, glacial acetic acid.
Embodiment 2
20.03g7-ACA is added in the four-hole bottle of 500mL, 150mL dichloroethanes is stirred to react 15min, temperature control to -10
DEG C~-25 DEG C, tetramethylguanidine 10.1mL is added dropwise, about 15min is added dropwise, continues to stir 30min, until 7-ACA all dissolves, drop
- 30 DEG C of temperature is spare；Addition 150mL dichloroethanes in the four-hole bottle of another 500mL, 23.69g tetrazoleacetic acid, 41.5mLN,
N- dimethyl acetamide, stirs 15min by -20 DEG C~-35 DEG C of temperature control, and 10mL triethylamine is added dropwise with about 20min, finishes stirring
15min is added dropwise 10mL pivaloyl chloride with about 30min, stirs 2h；< -30 DEG C of temperature control, 7-ACA lysate is added dropwise to tetrazole
In acetic acid mixed anhydride, it is stirred to react 1h, then 10~35 DEG C of temperature control, 200mL water is added, adjusts pH7.0-7.5, stirring with triethylamine
15min is hydrolyzed, water phase is collected, with active carbon decoloring, filtering is added 10% hydrochloric acid and adjusts pH to 1.5~2.5, then by system
Temperature is down to 0~5 DEG C of stirring 30min, filters, leaches filter cake with methylene chloride 100mL, refilter, 40 DEG C of filter cake baking oven subtract
Dry 4h is pressed dry, weighing obtains product 26.57g.The yield for the target product made in the embodiment is 60.77%, HPLC purity
It is 99.26%.
Embodiment 3
Be added 20.12g7-ACA in the four-hole bottle of 500mL, 150mL toluene is stirred to react 15min, temperature control to -25 DEG C~-
35 DEG C, tetramethylguanidine 12.4mL is added dropwise, about 15min is added dropwise, continues to stir 30min, until 7-ACA all dissolves, cooling -30
It is DEG C spare；150mL toluene, 23.16g tetrazoleacetic acid, 40.8mLN, N- dimethyl second are added in the four-hole bottle of another 500mL
Amide, stirs 15min by -35 DEG C~-40 DEG C of temperature control, and 10mL triethylamine is added dropwise with about 20min, stirring 15min is finished, with about
10mL pivaloyl chloride is added dropwise in 30min, stirs 2h；< -30 DEG C of temperature control, 7-ACA lysate is added dropwise in tetrazoleacetic acid mixed anhydride,
It being stirred to react 1h, then 10-35 DEG C of temperature control, 200mL water is added, adjusts pH8.0~8.5 with triethylamine, stirring hydrolyzes 15min,
Water phase is collected, with active carbon decoloring, filtering is added 10% hydrochloric acid and adjusts pH to 1.5~2.5, system temperature is then down to 0~
5 DEG C of stirring 30min are filtered, are leached filter cake with methylene chloride 100mL, refilter, and 40 DEG C of filter cake baking oven are dried under reduced pressure 4h, are claimed
Measure product 27.97g.The yield for the target product made in the embodiment is that 64.63%, HPLC purity is 99.35%.
Embodiment 4
10.04g7-ACA is added in the four-hole bottle of 500mL, 150mL methylene chloride is stirred to react 15min, temperature control to -25
DEG C~-35 DEG C, tetramethylguanidine 5.0mL is added dropwise, about 10min is added dropwise, continues to stir 20min, until 7-ACA all dissolves, drop
- 30 DEG C of temperature is spare；Addition 150mL methylene chloride in the four-hole bottle of another 500mL, 11.72g tetrazoleacetic acid, 20.1mLN,
N- dimethyl acetamide, stirs 15min by -30 DEG C~-40 DEG C of temperature control, and 5mL triethylamine is added dropwise with about 10min, finishes stirring
10min is added dropwise 5mL pivaloyl chloride with about 20min, stirs 1h；< -30 DEG C of temperature control, 7-ACA lysate is added dropwise to tetrazole second
In acid-mixed acid anhydride, it is stirred to react 30min, then 10~15 DEG C of temperature control, 100mL water is added, adjusted pH9.0~9.5 with triethylamine, stir
Hydrolysis 15min is mixed, water phase is collected, with active carbon decoloring, filtering is added 10% hydrochloric acid and adjusts pH to 1.5~2.5, then by body
It is that temperature is down to 0~5 DEG C of stirring 30min, filters, leach filter cake with methylene chloride 100mL, refilter, filter cake is with 40 DEG C of baking oven
It is dried under reduced pressure 4h, weighing obtains product 11.58g.The yield for the target product made in the embodiment is that 53.22%, HPLC is pure
Degree is 99.38%.
Embodiment 5
20.15g7-ACA is added in the four-hole bottle of 500mL, 150mL methylene chloride is stirred to react 15min, and temperature control is to -5 DEG C
~-15 DEG C, tetramethylguanidine 10.1mL is added dropwise, about 15min is added dropwise, continues to stir 30min, until 7-ACA all dissolves, drop
- 30 DEG C of temperature is spare；Addition 150mL methylene chloride in the four-hole bottle of another 500mL, 23.79g tetrazoleacetic acid, 40.5mLN,
N- dimethyl acetamide, stirs 15min by -10 DEG C~-20 DEG C of temperature control, and 10mL triethylamine is added dropwise with about 20min, finishes stirring
15min is added dropwise 10mL pivaloyl chloride with about 30min, stirs 2h；< -30 DEG C of temperature control, 7-ACA lysate is added dropwise to tetrazole
In acetic acid mixed anhydride, it is stirred to react 1h, then 10~35 DEG C of temperature control, 200mL water is added, adjusts pH10.0 with saturated sodium carbonate solution
~10.5, stirring hydrolysis 15min collect water phase, and with active carbon decoloring, filtering is added 10% hydrochloric acid and adjusts pH to 1.5~2.5,
Then system temperature is down to 0~5 DEG C of stirring 30min, filters, leaches filter cake with methylene chloride 100mL, refilter, filter cake is used
40 DEG C of baking oven are dried under reduced pressure 4h, and weighing obtains product 26.38g.The yield for the target product made in the embodiment is
60.04%, HPLC purity are 99.16%.
Embodiment 6
20.01g7-ACA is added in the four-hole bottle of 500mL, 150mL methylene chloride is stirred to react 15min, temperature control to -15
DEG C~-25 DEG C, tetramethylguanidine 9.6mL is added dropwise, about 15min is added dropwise, continues to stir 30min, until 7-ACA all dissolves, drop
- 30 DEG C of temperature is spare；Addition 150mL methylene chloride in the four-hole bottle of another 500mL, 23.32g tetrazoleacetic acid, 40.3mLN,
N- dimethyl acetamide, stirs 15min by -20 DEG C~-30 DEG C of temperature control, and 10mL triethylamine is added dropwise with about 20min, finishes stirring
15min is added dropwise 10mL pivaloyl chloride with about 30min, stirs 2h；< -30 DEG C of temperature control, 7-ACA lysate is added dropwise to tetrazole
In acetic acid mixed anhydride, it is stirred to react 1h, then 10~35 DEG C of temperature control, 200mL water is added, adjusts pH6.0 with saturated sodium carbonate solution
~6.5, stirring hydrolysis 15min collect water phase, and with active carbon decoloring, filtering is added 10% sulfuric acid and adjusts pH to 1.5~2.5,
Then system temperature is down to 0~5 DEG C of stirring 30min, filters, leaches filter cake with methylene chloride 100mL, refilter, filter cake is used
40 DEG C of baking oven are dried under reduced pressure 4h, and weighing obtains product 26.38g.The yield for the target product made in the embodiment is
60.04%, HPLC purity are 99.16%.
Embodiment 7
20.17g7-ACA is added in the four-hole bottle of 500mL, 150mL methylene chloride is stirred to react 15min, temperature control to -25
DEG C~-35 DEG C, tetramethylguanidine 9.4mL is added dropwise, about 15min is added dropwise, continues to stir 30min, until 7-ACA all dissolves, drop
- 30 DEG C of temperature is spare；Addition 150mL methylene chloride in the four-hole bottle of another 500mL, 23.43g tetrazoleacetic acid, 40.4mLN,
N- dimethyl acetamide, stirs 15min by -30 DEG C~-40 DEG C of temperature control, and 10mL triethylamine is added dropwise with about 20min, finishes stirring
15min is added dropwise 10mL pivaloyl chloride with about 30min, stirs 2h；< -30 DEG C of temperature control, 7-ACA lysate is added dropwise to tetrazole
In acetic acid mixed anhydride, it is stirred to react 1h, then 10~35 DEG C of temperature control, 200mL water is added, adjusted pH8.0~8.5 with triethylamine, stir
Hydrolysis 15min is mixed, water phase is collected, with active carbon decoloring, filtering is added 10% glacial acetic acid and adjusts pH to 1.5~2.5, then will
System temperature is down to 0~5 DEG C of stirring 30min, filters, leaches filter cake with methylene chloride 100mL, refilter, filter cake baking oven 40
It DEG C is dried under reduced pressure 4h, weighing obtains product 25.68g.The yield for the target product made in the embodiment is 58.90%, HPLC
Purity is 99.46%.
Gained Cefazolin acetoxyl group analog is further purified: the first step, and Cefazolin acetoxyl group is similar
The crude product of object is added to the water, and then adjusts pH to being completely dissolved.PH adjusting agent can be sodium carbonate, sodium bicarbonate, potassium carbonate, carbon
The strong base-weak acid salts such as potassium hydrogen phthalate.Second step, it is 1.0~3.0 that the solution that the first step is obtained, which adjusts pH, and solid is precipitated, filters, wash
Wash, dry to get finished product --- Cefazolin acetoxyl group analog.PH adjusting agent can be dilute hydrochloric acid, dilute sulphur in this step
The inorganic acids such as acid, glacial acetic acid.
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 (10)
1. a kind of preparation method of Cefazolin acetoxyl group analog, it is characterised in that: this method is with 7-ACA solution and four nitrogen
Zole acetic acid mixed anhydride solution is reaction raw materials, by carrying out match control to raw material proportioning, reaction temperature, system pH value, is made
Cefazolin acetoxyl group analog finished product；This method comprises the following steps:
A, the preparation of 7-ACA solution:
Under the conditions of being not more than -5 DEG C of temperature, take the i.e. 7-ACA dissolution of raw material of chemical compounds I into organic solvent, then again to it
In tetramethylguanidine is slowly added dropwise, until 7-ACA dissolution completely until, obtain 7-ACA solution, it is spare；
B, the preparation of tetrazoleacetic acid mixed anhydride solution:
Under the conditions of being not more than -5 DEG C of temperature, compound ii i.e. tetrazoleacetic acid is taken to be dissolved into organic solvent, then to it
Middle addition n,N-dimethylacetamide, triethylamine and pivaloyl chloride obtain tetramethylguanidine mixed anhydride solution, spare；
C, the synthesis of Cefazolin acetoxyl group analog:
C-1,7-ACA solution obtained by step A is added drop-wise in tetrazoleacetic acid mixed anhydride solution obtained by step B, is stirred to react, then
Add water-extraction and collects water phase；
C-2, the pH of upper step acquired solution is adjusted to 6.0-10.5 with alkali, reaction is hydrolyzed；
Hydrolyzate is collected after C-3, hydrolysis and carries out decolorization, and pH value of solution is then adjusted to 1.5-2.5 with acid, is filtered
Primary product；
The stirring of Primary product organic solvent obtained by C-4, upper step leaches, and using filter-washing-drying, obtains compound III, i.e.,
Cefazolin acetoxyl group analog finished product.
2. a kind of preparation method of Cefazolin acetoxyl group analog according to claim 1, it is characterised in that: the party
Method further includes following steps:
D, Cefazolin acetoxyl group analog obtained by step C is purified:
D-1, the crude product of Cefazolin acetoxyl group analog obtained by step C is added to the water, then adds strong base-weak acid salt extremely
Dissolution is complete；
D-2, upper step acquired solution is adjusted pH using inorganic acid is 1.5~2.5, solid is precipitated, filtering-washing-drying obtains head
Spore azoles woods acetoxyl group analog sterling.
3. a kind of preparation method of Cefazolin acetoxyl group analog according to claim 1, it is characterised in that: step
In A, -5 DEG C~-25 DEG C of operating process temperature control, in -30 DEG C or less preservation solution for standby after the completion of operation.
4. a kind of preparation method of Cefazolin acetoxyl group analog according to claim 1, it is characterised in that: step
In B, -10 DEG C~-30 DEG C of operating process temperature control, in -30 DEG C or less preservation solution for standby after the completion of operation.
5. a kind of preparation method of Cefazolin acetoxyl group analog according to claim 1, it is characterised in that: step
In C, -30 DEG C of initial temperature control hereinafter, plus 10~35 DEG C of temperature control before water, 10~20 DEG C of temperature control after decolorization, pH value of solution is adjusted to 1.5
0~5 DEG C of temperature control after~2.5, after the reaction was completed, filter cake is dried under reduced pressure to obtain finished product at 30~50 DEG C.
6. a kind of preparation method of Cefazolin acetoxyl group analog according to claim 1, it is characterised in that: step
In A, the 7-ACA, organic solvent, tetramethylguanidine three usage ratio are as follows: 20g:(100~200mL): (4~16mL)；Step
In rapid B, in the tetrazoleacetic acid, organic solvent, the usage ratio of n,N-dimethylacetamide, triethylamine, pivaloyl chloride be
23.5g:(100~200mL): (30~50mL): (4~16mL): (4~16mL).
7. a kind of preparation method of Cefazolin acetoxyl group analog according to claim 1, it is characterised in that: step
In A, the 7-ACA, organic solvent, tetramethylguanidine three usage ratio are as follows: 20g:150mL:10mL；In step B, described four
In nitrogen zole acetic acid, organic solvent, the usage ratio of n,N-dimethylacetamide, triethylamine, pivaloyl chloride be 23.5g:150mL:
40mL:11mL:11mL。
8. a kind of preparation method of Cefazolin acetoxyl group analog according to claim 1, it is characterised in that: step
The usage ratio of organic solvent is 1:(0.8~1.2 in A and step B) v/v.
9. a kind of preparation method of Cefazolin acetoxyl group analog according to claim 1, it is characterised in that: step
In A and step B, the organic solvent is one of methylene chloride, toluene, dichloroethanes or multiple combinations.
10. a kind of preparation method of Cefazolin acetoxyl group analog according to claim 1, it is characterised in that: step
In rapid C, alkali used in pH is adjusted as the combination of one or more of sodium carbonate, sodium bicarbonate, triethylamine；Adjust acid used in pH
For the combination of one or more of hydrochloric acid, sulfuric acid.
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| CN201811325839.7A CN109293679A (en) | 2018-11-08 | 2018-11-08 | A kind of preparation method of Cefazolin acetoxyl group analog |
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| CN201811325839.7A CN109293679A (en) | 2018-11-08 | 2018-11-08 | A kind of preparation method of Cefazolin acetoxyl group analog |
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| CN201811325839.7A Pending CN109293679A (en) | 2018-11-08 | 2018-11-08 | A kind of preparation method of Cefazolin acetoxyl group analog |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109369682A (en) * | 2018-12-12 | 2019-02-22 | 河北合佳医药科技集团股份有限公司 | A kind of preparation method of Cefazolin -3- methyl analogue |
| CN110776520A (en) * | 2019-10-30 | 2020-02-11 | 广州牌牌生物科技有限公司 | Preparation method of cefazolin sodium impurity G |
| CN110790775A (en) * | 2019-10-30 | 2020-02-14 | 广州牌牌生物科技有限公司 | Preparation method of cefazolin sodium impurity B |
| CN111118098A (en) * | 2019-12-25 | 2020-05-08 | 哈尔滨合佳制药有限公司 | Preparation method of 3-hydroxymethyl cefazolin |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102977122A (en) * | 2012-10-08 | 2013-03-20 | 江苏德峰药业有限公司 | Ceftezole acid preparation method |
| CN104910188A (en) * | 2015-05-26 | 2015-09-16 | 齐鲁安替制药有限公司 | Synthetic method of cefazolin acid |
-
2018
- 2018-11-08 CN CN201811325839.7A patent/CN109293679A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102977122A (en) * | 2012-10-08 | 2013-03-20 | 江苏德峰药业有限公司 | Ceftezole acid preparation method |
| CN104910188A (en) * | 2015-05-26 | 2015-09-16 | 齐鲁安替制药有限公司 | Synthetic method of cefazolin acid |
Non-Patent Citations (1)
| Title |
|---|
| PALOMO-COLL, ALBERTO等: "Semisynthetic cephalosporins. VIII. Efficient procedure for C"-3 substitution and C-7 N-acylation of 7-aminocephalosporanic acid (7-ACA):synthesis of cefazolin antibiotic and related compounds", 《TETRAHEDRON》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109369682A (en) * | 2018-12-12 | 2019-02-22 | 河北合佳医药科技集团股份有限公司 | A kind of preparation method of Cefazolin -3- methyl analogue |
| CN110776520A (en) * | 2019-10-30 | 2020-02-11 | 广州牌牌生物科技有限公司 | Preparation method of cefazolin sodium impurity G |
| CN110790775A (en) * | 2019-10-30 | 2020-02-14 | 广州牌牌生物科技有限公司 | Preparation method of cefazolin sodium impurity B |
| CN111118098A (en) * | 2019-12-25 | 2020-05-08 | 哈尔滨合佳制药有限公司 | Preparation method of 3-hydroxymethyl cefazolin |
| CN111118098B (en) * | 2019-12-25 | 2023-09-29 | 哈尔滨合佳制药有限公司 | Preparation method of 3-hydroxymethyl cefazolin |
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