CN109575048B - Preparation method of cefotaxime sodium - Google Patents

Preparation method of cefotaxime sodium Download PDF

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CN109575048B
CN109575048B CN201811604072.1A CN201811604072A CN109575048B CN 109575048 B CN109575048 B CN 109575048B CN 201811604072 A CN201811604072 A CN 201811604072A CN 109575048 B CN109575048 B CN 109575048B
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cefotaxime
acid
solvent
preparation
reagent
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CN109575048A (en
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于永宏
侯微
王凤一
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Shanghai Pharma Xinya Pharmaceutical Co ltd
LIAONING MEDYA PHARMACEUTICAL CO Ltd
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LIAONING MEDYA PHARMACEUTICAL CO Ltd
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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
    • 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
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Organic Chemistry (AREA)
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Abstract

The invention provides a preparation method of cefotaxime sodium, which is characterized by comprising the following steps: after protecting the active group of 7-aminocephalosporanic acid by a silanization reagent, carrying out condensation reaction with AE-active ester to generate cefotaxime acid containing a protecting group; the cefotaxime acid containing the protecting group is deprotected by a deprotection agent, and then sequentially acidified and crystallized through a water phase to obtain cefotaxime acid; the cefotaxime acid is subjected to salification and solvent crystallization to obtain a pure cefotaxime sodium product. The whole process reduces the degradation process of the product, obviously improves the product quality, improves the market competitiveness of the product and further guarantees the safety of medication.

Description

Preparation method of cefotaxime sodium
Technical Field
The invention relates to the field of organic synthesis, in particular to a preparation method of cefotaxime sodium serving as an antibacterial drug.
Background
Cefotaxime sodium is known by the chemical name of (6R,7R) -3- [ (acetoxy) methyl ] -7- [ (2-amino-4-thiazolyl) - (methoxyimino) acetamido ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid sodium. Is a cephalosporin antibiotic product for the third generation injection.
At present, the technology of the variety is mainly that 7-aminocephalosporanic acid and 2-methoxyimino-2- (2-amino-4-thiazolyl) - (z) -thioacetic acid phenylhydrazine thiazole ester are added with cefotaxime acid in solvents such as dichloromethane or 2-methyltetrahydrofuran, then solvents such as organic alcohol are added, diluted acid is dripped to adjust PH crystallization, and the cefotaxime acid solid after complete drying is obtained through centrifugal separation.
Then, the dried solid pure product is made into sodium salt in an aqueous solution containing sodium acetate or an organic solvent of sodium isooctanoate, and then the cefotaxime sodium is obtained by crystallization with a solvent such as acetone or isopropanol.
In the process, active functional groups such as 7-ACA amino carboxyl and the like are not protected, so that the reaction process is easy to oxidize and degrade, and impurities are more and higher. And the obtained product has high color grade and is not beneficial to subsequent production, research and utilization.
Disclosure of Invention
The invention aims to overcome the defects in the prior art, 7-ACA amino and carboxyl are firstly protected and then condensed with AE-active ester to form cefotaxime acid, then weak base aqueous solution is added for deprotection and then is acidified and crystallized, then cefotaxime acid becomes sodium salt in anhydrous alcohol sodium solution, and organic solvent is used for crystallization to obtain the product with quality superior to that of products sold in the market and originally researched. The process reduces the emission of organic matters, so that the process is energy-saving and environment-friendly, and the product quality is obviously improved.
In order to achieve the above object, the present invention provides a method for preparing cefotaxime sodium, which is characterized in that: after protecting the active group of 7-aminocephalosporanic acid by a silanization reagent, carrying out condensation reaction with AE-active ester to generate cefotaxime acid containing a protecting group;
the cefotaxime acid containing the protecting group is deprotected by a deprotection agent, and then sequentially acidified and crystallized through a water phase to obtain cefotaxime acid;
the cefotaxime acid is subjected to salification and solvent crystallization to obtain a pure cefotaxime sodium product.
Further, the preparation method of cefotaxime sodium provided by the invention also has the following characteristics:
the group protection reaction is carried out in the environment of taking halogenated hydrocarbon as a solvent; such as: chloroform, dichloromethane, carbon tetrachloride, and the like.
The deprotection agent is one or more of hydroxide, carbonate or bicarbonate of alkali metal or alkaline earth metal (such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, etc.), and polyamine (such as triethylamine, diethylamine, ethylenediamine, etc.);
the silanization reagent is selected from hexamethyl disilaurea, HMDS, BSA, BSU or silanization reagents with similar structures;
the reagent for the salt forming reaction is selected from organic sodium salt with the carbon atom number not more than 20. Typically, the organic sodium salt is an alkyl acid sodium salt, such as: sodium acetate or sodium isooctanoate, and the like. Preferably, such sodium salts are dissolved or miscible in alcoholic solvents for reaction.
Further, the preparation method of cefotaxime sodium provided by the invention also has the following characteristics: namely, the specific process steps are as follows:
s1, adding a silanization reagent and 7-aminocephalosporanic acid into a halogenated hydrocarbon solvent, heating, refluxing, dissolving and clearing, condensing with AE-active ester at the temperature of 10-30 ℃, and reacting for 10-24 hours to obtain cefotaxime acid containing a protective group;
s2, adding a deprotection agent to extract a product of S1 to obtain a water phase, controlling the temperature below 30 ℃, adjusting the pH value to 2.8-3.0, and crystallizing to obtain a crude product of cefotaxime acid;
the specific reaction equation is as follows:
Figure BDA0001923192840000031
s3, sequentially adding a salifying reagent and a cefotaxime acid crude product, stirring for dissolving, and adding a crystallization reagent for crystal growth.
The crystallization reagent can be one or more of high polar solvents such as esters (methyl acetate, ethyl acetate, etc.), ketones (acetone, etc.), ethers, alcohols, etc.
The specific equation is as follows:
Figure BDA0001923192840000032
further, the preparation method of cefotaxime sodium provided by the invention also has the following characteristics: namely, the molar ratio of the 7-aminocephalosporanic acid to the silanization reagent is 1: 1.05-2.0;
the molar ratio of the 7-aminocephalosporanic acid to the silanization reagent is 1: 1.5-2.0;
the weight ratio of the 7-aminocephalosporanic acid to the silanization reagent is 1.5-2.0;
the dosage of the silanization reagent is 60 to 80 percent of the total weight of the 7-aminocephalosporanic acid and the AE-active ester;
the mass ratio of the 7-aminocephalosporanic acid to the AE-active ester is 1: 1-5;
the mass ratio of the 7-aminocephalosporanic acid to the deprotection agent is 1: 0.5-5;
the adding amount of the deprotection agent is the adding end point when the pH value of the reaction system is adjusted to be in the range of 7.0-9.0;
the mass ratio of the cefotaxime acid to the salifying reagent is 1: 0.3-0.6;
the molar ratio of the salifying reagent to the cefotaxime acid is 1: 1.0-2.0.
Further, the preparation method of cefotaxime sodium provided by the invention also has the following characteristics: that is, the step of S2 is carried out at a temperature of 20 ℃ or lower;
the deprotection agent is mixed and dissolved in water for reaction;
the amount of the water is 0.3-2.5 times of the amount of the solvent in the S1.
The specific steps can be as follows:
s2-1, after the reaction is finished, cooling to below 20 ℃, and adding sodium bicarbonate/pure water to quench the reaction; the amount of the water is 0.3-2.5 times of the amount of the solvent.
S2-2, adding an alkaline aqueous solution for deprotection, acidifying and crystallizing, centrifugally separating, washing with a detergent, and filtering to obtain a wet product, namely cefotaxime acid; the process generally comprises the steps of extracting a solid product by a centrifugal mode after a period of crystal washing, and removing the residue of impurities by a mode of washing for multiple times, wherein the solvent for washing can be water, alcohol, ketone, ether and other higher reagents.
Or
S2-1, after the reaction is finished, cooling to below 20 ℃, and adding pure water to quench the reaction;
s2-2, decoloring for 5-30min by using activated carbon;
s2-3, adding an aqueous alkali solution for acidification and crystallization, centrifugally separating, washing with a detergent, and filtering to obtain a wet product, namely cefotaxime acid.
The above detergent is selected from one or more of pure water, ketone solvent (acetone, etc.), alcohol solvent (methanol, ethanol, propanol, butanol, etc.), and ether solvent (diethyl ether, tetrahydrofuran, dioxane, etc.).
Further, the preparation method of cefotaxime sodium provided by the invention also has the following characteristics: that is, a cosolvent, an acylation catalyst or an activator is further added in the amount of 0.01 to 1 times of the total weight of the reactants in S2.
Such as: CDI, EDCI, DIC, DCC, DMAP, HOBt, DMF, DMA, HATU, HBTU, NMM, TFA, TEA and the like.
Further, the preparation method of cefotaxime sodium provided by the invention also has the following characteristics: that is, the step of S3 is performed in a mixed solvent of one or more of dimethyl carbonate, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, ethanol, methanol, acetone, n-butanol, triethylamine, diethylamine, water, DMF, ethyl acetate, and isopropanol;
mixing the salt forming agent and alcohol and then carrying out salt forming reaction;
the dosage of the alcohol is 2.0 to 4.0 times of that of the cefotaxime acid.
The specific processing procedure in S3 described above may be as follows:
s3-1, salifying cefotaxime acid and sodium alcohol solution; the dosage of the alcohol is 2.0 to 4.0 times of that of the cefotaxime acid.
S3-2, dropwise adding the cefotaxime sodium solution into an organic solvent for turbid crystallization. The organic solvent is one or more of ketone solvent, alcohol solvent and ester solvent to obtain the target product.
Or
S3-1, salifying cefotaxime acid and sodium alcohol solution, and adding an organic solvent for crystallization;
s3-2, decoloring for 5-30min by using activated carbon;
s3-3, dropwise adding an organic solvent for crystallization, and crystallizing by adopting one or more of a ketone solvent, an alcohol solvent and an ester solvent to obtain the target product.
The solvent in the above reaction process can be selected from dimethyl carbonate, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, ethanol, methanol, acetone, n-butanol, triethylamine, diethylamine, water, DMF, ethyl acetate, isopropanol, etc.
Further, the preparation method of cefotaxime sodium provided by the invention also has the following characteristics: namely, the organic solvent is selected from one or more of ketone solvent, alcohol solvent and ester solvent.
Further, the preparation method of cefotaxime sodium provided by the invention also has the following characteristics: that is, the processes of S2 and S3 are further performed by a step of decolorizing with activated carbon.
The invention has the following functions and effects:
the cefotaxime sodium produced by the method has high content and good color grade, known impurities are smaller than those of products in the original research and the market, and the unknown impurities can be controlled to be below 0.05 percent; in the method, before the synthesis of cefotaxime acid, a silanization reagent is used for protecting the amino carboxyl of 7-aminocephalosporanic acid, when the cefotaxime sodium is synthesized, the cefotaxime acid and sodium form salt under anhydrous condition, and then solvent crystallization is carried out to obtain the cefotaxime sodium product. The whole process reduces the degradation process of the product, obviously improves the product quality, improves the market competitiveness of the product and further guarantees the safety of medication.
Drawings
FIG. 1. map of example 1-1;
FIG. 2 is a map of example 1-2;
FIG. 3 is a map of example 2-1;
FIG. 4 is a map of example 2-2;
FIG. 5 is a map of example 3-1;
FIG. 6 is a map of example 3-2.
Detailed Description
Examples 1-1,
500ml of chloroform, 20g of 7-aminocephalosporanic acid and HMDS22g were added at room temperature. Heating and refluxing for 5-6.0hr, cooling to below 20 deg.C, adding 28g AE-active ester, and condensing for 12-15 hr.
Then 300ml of 8% sodium bicarbonate aqueous solution is added for extraction, and 2g of activated carbon is added to the aqueous phase for decolorization for 20min and filtration is carried out. Controlling the temperature of the filtrate to be below 30 ℃, adding 130ml of acetone and 65ml of n-butanol, dropwise adding dilute acid solution to adjust the pH to be 2.8-3.0, and separating out crystals. Filtering, washing a filter cake with pure water, draining, washing with acetone, draining, drying and discharging to obtain a cefotaxime acid crude product with the yield of 85%.
The purity of the high-pressure liquid phase is 99.6 percent, and the color is yellow green and is less than or equal to 2 #. (see the attached figure 1 for details)
Examples 1 to 2,
300ml of absolute methanol and 15g of sodium acetate were added to the reactor, and dissolved by stirring. Then, 45g of cefotaxime acid crude product is added, and the mixture is stirred to dissolve. Adding activated carbon 2g, decolorizing for 20min, and filtering. The filtrate was added acetone dropwise to turbidity. Growing the grains for 60 min. Then, later-stage acetone is dripped, the temperature is reduced to 0-5 ℃, and crystal growth is carried out for 60 min. And (5) carrying out suction filtration and drying to obtain cefotaxime sodium with the yield of 87%.
The purity of the high-pressure liquid phase is 99.6 percent, and the color is yellow green and is less than or equal to 2 #. (see the attached figure 2 for details)
Example 2-1,
300ml of dichloromethane, 20g of 7-aminocephalosporanic acid and 35g of BSU are added at room temperature. Heating and refluxing for 5-6.0hr, cooling to below 20 deg.C, adding AE-active ester 30g, and condensing for 12-15 hr.
Then, 200ml of 6% sodium hydroxide aqueous solution was added thereto for extraction, and the aqueous phase was decolorized with 2g of activated carbon for 20min and filtered. Controlling the temperature of the filtrate below 30 ℃, adding 130ml of tetrahydrofuran and 65ml of normal butanol, dropwise adding dilute acid solution to adjust the pH value to 2.8-3.0, and separating out crystals. Filtering, washing a filter cake with pure water, draining, washing with tetrahydrofuran, draining, drying and discharging to obtain a cefotaxime acid crude product with the yield of 88%.
The purity of the high-pressure liquid phase is 99.6 percent, and the color is yellow green and is less than or equal to 2 #. (see the attached figure 3 for details)
Examples 2-2,
150ml of ethanol was added to the reactor, and 26g of sodium isooctanoate was added and dissolved by stirring. Then adding 45g of cefotaxime acid crude product, dropwise adding a proper amount of triethylamine, and stirring to dissolve the solution. Adding activated carbon 2g, decolorizing for 20min, and filtering. The filtrate was added dropwise with ethanol until cloudy. Growing the grains for 60 min. Then later-stage ethanol is dripped, the temperature is reduced to 0-5 ℃, and crystal growth is carried out for 60 min. And (5) carrying out suction filtration and drying to obtain cefotaxime sodium with the yield of 86%.
The purity of the high-pressure liquid phase is 99.5 percent, and the color is yellow green and is less than or equal to 2 #. (see the attached figure 4 for details)
Example 3-1,
At room temperature, 300ml of dichloromethane, 150ml of carbon tetrachloride, 20g of 7-aminocephalosporanic acid and 30g of BSA are added. Heating and refluxing for 5-6.0hr, cooling to below 20 deg.C, adding 28g AE-active ester, and condensing for 12-15 hr.
Then 270ml of 10% sodium carbonate aqueous solution is added for extraction, and 2g of activated carbon is added to the aqueous phase for decolorization for 20min and filtration is carried out. Controlling the temperature of the filtrate to be below 30 ℃, adding 130ml of tetrahydrofuran and 65ml of isopropanol, dropwise adding dilute acid solution to adjust the pH value to be 2.8-3.0, and precipitating crystals. Filtering, washing a filter cake with pure water, draining, washing with tetrahydrofuran and isopropanol, draining, drying and discharging to obtain a cefotaxime acid crude product with the yield of 88%.
The purity of the high-pressure liquid phase is 99.6 percent, and the color is yellow green and is less than or equal to 2 #. (see FIG. 5 for details)
Examples 3 to 2,
200ml of anhydrous methanol and 26g of sodium isooctanoate were added to the reactor, and the mixture was dissolved by stirring. Then, 45g of cefotaxime acid crude product is added, and the mixture is stirred to dissolve. Adding activated carbon 2g, decolorizing for 20min, and filtering. The filtrate was added dropwise with ethyl acetate until cloudy. Growing the grains for 60 min. Then, ethyl acetate is dripped, the temperature is reduced to 0-5 ℃, and the crystal growth is carried out for 60 min. And (5) carrying out suction filtration and drying to obtain cefotaxime sodium with the yield of 87%.
The purity of the high-pressure liquid phase is 99.6 percent, and the color is yellow green and is less than or equal to 2 #. (see FIG. 6 for details).

Claims (8)

1. A preparation method of cefotaxime sodium is characterized by comprising the following steps:
the specific process steps are as follows:
s1, adding a silanization reagent and 7-aminocephalosporanic acid into a halogenated hydrocarbon solvent, heating up, refluxing and dissolving to be clear, simultaneously protecting active groups of amino and carboxyl of the 7-aminocephalosporanic acid by using the silanization reagent, and reacting with AE-active ester at the temperature of 10-30 ℃ for 10-24 hours to obtain cefotaxime acid containing a carboxyl protecting group;
s2, adding a deprotection agent to extract a product of S1 to obtain a water phase, controlling the temperature below 30 ℃, adjusting the pH value to 2.8-3.0, and crystallizing to obtain a crude product of cefotaxime acid;
s3, sequentially adding a salifying reagent and a cefotaxime acid crude product, stirring for dissolving, and adding a solvent for crystallization to obtain a cefotaxime sodium pure product;
wherein, the group protection reaction is carried out in the environment of taking halogenated hydrocarbon as a solvent;
the deprotection agent is one or more of hydroxide, carbonate or bicarbonate of alkali metal or alkaline earth metal and polyamine;
the silylating agent is selected from hexamethyldisilaurea, hexamethyldisilazane HMDS, bis (trimethylsilyl) acetamide BSA, bis (trimethylsilyl) urea BSU;
the salifying reagent is selected from organic sodium salts with the carbon atom number not more than 20.
2. A process for the preparation of cefotaxime sodium according to claim 1, wherein: the molar ratio of the 7-aminocephalosporanic acid to the silanization reagent is 1: 1.05-2.0;
the weight ratio of the 7-aminocephalosporanic acid to the silanization reagent is 1.5-2.0;
the dosage of the silanization reagent is 60-80% of the total weight of the 7-aminocephalosporanic acid and the AE-active ester;
the mass ratio of the 7-aminocephalosporanic acid to the AE-active ester is 1: 1-5;
the mass ratio of the 7-aminocephalosporanic acid to the deprotection agent is 1: 0.5-5;
the addition amount of the deprotection agent takes the pH value of a reaction system within the range of 7.0-9.0 as an addition end point;
the mass ratio of the cefotaxime acid to the salifying reagent is 1: 0.3-0.6;
the molar ratio of the salifying reagent to the cefotaxime acid is 1: 1.0-2.0.
3. A process for the preparation of cefotaxime sodium according to claim 1, wherein: said S2 is carried out at a temperature below 20 ℃;
the deprotection agent is mixed and dissolved in water and then reacts;
the dosage of the water is 0.3 to 2.5 times of the dosage of the solvent in the S1.
4. A process for the preparation of cefotaxime sodium according to claim 1, wherein: and the crystal precipitated in the S2 is washed at least once by one or more solvents of water, alcohols, ketones and ethers.
5. A process for the preparation of cefotaxime sodium according to claim 1, wherein: the step of S3 is carried out in one or a mixture of more of dimethyl carbonate, dichloromethane, trichloromethane, carbon tetrachloride, tetrahydrofuran, ethanol, methanol, acetone, n-butanol, triethylamine, diethylamine, water, DMF, ethyl acetate and isopropanol;
mixing the salt forming agent and alcohol and then carrying out salt forming reaction;
the dosage of the alcohol is 2.0 to 4.0 times of that of the cefotaxime acid.
6. A process for the preparation of cefotaxime sodium according to claim 1, wherein: the solvent is selected from one or more of ketone solvent, alcohol solvent and ester solvent.
7. A process for the preparation of cefotaxime sodium according to claim 1, wherein: and a cosolvent, an acylation catalyst or an activating agent which accounts for 0.01-1 time of the total weight of the reactants is also added into the S3.
8. A process for the preparation of cefotaxime sodium according to claim 1, wherein: in the processes of S2 and S3, activated carbon is used for decoloring.
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CN110283187A (en) * 2019-07-10 2019-09-27 辽宁美亚制药有限公司 A kind of preparation method promoting Cefotaxime Sodium product quality
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CN114989194B (en) * 2022-06-07 2023-09-26 艾美科健（中国）生物医药有限公司 Method for reducing polymer in cefotaxime sodium
CN115232151A (en) * 2022-08-04 2022-10-25 辽宁美亚制药有限公司 New synthesis method of ceftriaxone sodium

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