CN109912625B - Process method for reducing ceftazidime impurity H - Google Patents
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Abstract
The invention provides a process method for reducing ceftazidime impurity H, which is characterized by comprising the following steps: the method comprises the steps of taking one or more of dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, acetonitrile and 2-methyltetrahydrofuran as a main solvent, taking tert-butyl alcohol or a mixed solvent of tert-butyl alcohol and methanol as a cosolvent, carrying out condensation reaction on 7-APCA and the active ester of the ceftazidime under an alkaline condition to generate the tert-butyl ester of the ceftazidime, and carrying out water treatment and solvent crystallization to obtain the tert-butyl ester of the ceftazidime. The product obtained by the method has impurity ceftazidime methyl ester (H) less than 0.1%, and unknown impurities can be controlled below 0.05%.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a preparation method of an antibacterial drug ceftazidime.
Background
The chemical name of ceftazidime is (6R,7R) -7- [ [ (2Z) -2- (2-amino-1, 3-thiazol-4-yl) -2- (1-hydroxy-2-methyl-1-oxopropan-2-yl) oxyacetamido ] amino ] -8-oxo-3- (pyridin-1-ylium-1-ylmethyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid. Is a cephalosporin antibiotic product for the third generation injection.
According to the structural formula analysis of ceftazidime methyl ester (H) contained in EP pharmacopoeia, the most probable impurity generated in the preparation process of ceftazidime is a trace amount of the impurity in the process link of synthesizing ceftazidime tert-butyl ester or in the raw material of ceftazidime active ester. The use of methanol as a solvent is controlled in the synthesis of active ester of the tadine and the synthesis of tert-butyl ester of the tadine by relevant research documents. The structure of ceftazidime impurity H is (6R,7R) -7- [ [ (2-amino-1, 3, 4-thiazol-4-yl) -2- (1-methoxy-2-methyl-1-oxoendolan-2-yl) oxyacetamido ] amino ] -8-oxo-3- (pyridin-1-ium-1-yl-methyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid; the teratogenic effect of the impurity is 25 times that of ceftazidime and the lethal effect of the impurity is 8 times that of the ceftazidime through zebrafish embryotoxicity experiments. Therefore, the ceftazidime impurity H should be strictly controlled.
Currently, the domestic synthesis of ceftazidime mainly comprises the steps of refluxing 7-aminocephalosporanic acid and a silanization reagent in a dichloromethane solvent, firstly carrying out amino carboxyl protection, then forming an iodide with iodotrimethylsilane, and then synthesizing 7-APCA (Acrylonitrile-Acrylonitrile) three-position intermediate with pyridine. Condensing 7-APCA in organic solvent such as dichloromethane/methanol and the like with active ester of the tadine to obtain tert-butyl ester of the tadine, acidifying the tert-butyl ester of the tadine in mixed solution of formic acid and hydrochloric acid to form hydrochloride of the tadine, adjusting the pH of the hydrochloride of the tadine in a proper amount of water for injection by using diluted alkali to dissolve the hydrochloride of the tadine, and then acidifying and crystallizing to obtain the target product of the ceftazidime.
In the above process, the process for producing ceftazidime methyl ester (H) is that the use of methanol as a solvent in the synthesis of the tert-butyl ester of the ceftazidime leads to the transesterification of the tert-butyl group in the side chain at the seven position with methanol. The US005831085A patent reports that the side chain at the seven position is condensed with an acid chloride reagent without the use of a tadine active ester. Namely synthesizing acyl chloride preparation by the side chain acid of the tadine and DFCCS, and then synthesizing the tertiarybutyl ester of the tadine with 7-APCA under the condition of low temperature, wherein the whole process requires ultralow temperature reaction, the industrial control difficulty is large, the cost is high, and the acyl chloride preparation is unstable.
Disclosure of Invention
The invention aims to overcome the defects in the technology, 7-APCA still adopts the current domestic general stable industrialized process, 7-APCA is condensed with the active ester of the tadine in the mixed solvent of dichloromethane, chloroform, tetrahydrofuran, acetonitrile, carbon tetrachloride, 2-methyltetrahydrofuran and the like and tert-butyl alcohol or methanol to form the tert-butyl ester of the tadine, and then the mixed solvent is added with pure water for treatment, and the solvent is crystallized. The ceftazidime tert-butyl ester synthesized by the process is salified in a mixed solution of formic acid and hydrochloric acid, and acetone is crystallized to obtain ceftazidime hydrochloride, and the ceftazidime methyl ester (H) is less than 0.1% by liquid phase analysis. The ceftazidime pentahydrate is continuously synthesized, and the impurity is still less than 0.1 percent through liquid phase analysis. The impurities of the product of domestic ceftazidime manufacturers are generally more than 0.2 percent, so the key process link of controlling the generation of the impurities by using the process method obviously improves the quality of the ceftazidime and reduces the adverse reaction and the toxic and side effect of the medicament.
In order to achieve the above object, the present invention provides a method for preparing ceftazidime tert-butyl ester, which is characterized in that: the method comprises the steps of taking one or more of dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, acetonitrile and 2-methyltetrahydrofuran as a main solvent, taking tert-butyl alcohol or a mixed solvent of tert-butyl alcohol and methanol as a cosolvent, carrying out condensation reaction on 7-APCA and the active ester of the ceftazidime under an alkaline condition to generate the tert-butyl ester of the ceftazidime, and carrying out water treatment and solvent crystallization to obtain the tert-butyl ester of the ceftazidime.
Further, the preparation method of ceftazidime tert-butyl ester provided by the invention also has the following characteristics: namely, the molar ratio of the 7-APCA to the active ester of the tadine is 1: 1.05-1.25; preferably 1: 1.15-1.20; the weight ratio is 1.4-1.5.
Further, the preparation method of ceftazidime tert-butyl ester provided by the invention also has the following characteristics: namely, the dosage of the cosolvent is 10 to 20 percent of the total weight of 7-APCA and the active ester of the tadine.
Further, the preparation method of ceftazidime tert-butyl ester provided by the invention also has the following characteristics: namely, the volume ratio of the main solvent to the cosolvent is 10-25: 1.
Further, the preparation method of ceftazidime tert-butyl ester provided by the invention also has the following characteristics: that is, when the cosolvent is a mixed solvent of tert-butyl alcohol and methanol,
the volume ratio of the tertiary butanol to the methanol is 5-10: 1.
Further, the preparation method of ceftazidime tert-butyl ester provided by the invention also has the following characteristics: namely, the specific process steps are as follows:
s1, adding a cosolvent into a main solvent, cooling to 0-10 ℃, adding 7-APCA and a tadine active ester, adjusting the pH value to 7-9, and controlling the temperature to react for 20-24 hours;
and S2, treating the reaction solution with pure water for 1-2 hours, and then carrying out solvent crystallization and washing procedures to obtain ceftazidime tert-butyl ester.
The reaction equation of the above reaction process is as follows:
further, the preparation method of ceftazidime tert-butyl ester provided by the invention also has the following characteristics: namely, the reagent for adjusting the pH is an alkaline agent, and polyamine is selected from the following: one or more of triethylamine, diethylamine, ethylenediamine, DMF, etc.
Further, the preparation method of ceftazidime tert-butyl ester provided by the invention also has the following characteristics: that is, the solvent for crystallization and the reagent for washing are selected from one or more of pure water, alcohols having 2 or more carbon atoms, ketones, and ethers.
In addition, the invention also provides a preparation method of ceftazidime hydrochloride, which is characterized by comprising the following steps: adding ceftazidime tert-butyl ester prepared by the method of any one of claims 1 to 8 into a mixed solution of formic acid and hydrochloric acid, reacting at the reaction temperature of 15-20 ℃ for 2-5 hours, and crystallizing by using an organic reagent to obtain ceftazidime hydrochloride;
wherein the volume ratio of the formic acid to the hydrochloric acid is 1: 0.5-1;
the dosage ratio of the mixed solution of the formic acid and the hydrochloric acid to the ceftazidime tert-butyl ester is as follows: adding 0.6-1.5 g of ceftazidime tert-butyl ester into each ml of mixed solution of formic acid and hydrochloric acid;
the organic reagent is selected from one or more of alcohols (propanol, butanol, isopropanol, etc.), ketones (acetone, etc.), and ether solvents (diethyl ether, tetrahydrofuran, dioxane, etc.) with carbon number greater than 2.
The reaction equation of the above reaction process is as follows:
in addition, the invention also provides a preparation method of the ceftazidime pentahydrate, which is characterized by comprising the following steps:
s1, adding ceftazidime hydrochloride prepared according to claim 9 after uniformly mixing water and an organic solvent;
s2, adjusting the pH value to 6.0-6.5 to enable the pH value to be clear;
s3, adding a decoloring agent for decoloring for 5-15 minutes;
and S4, dropwise adding phosphoric acid until crystallization is complete to obtain the ceftazidime pentahydrate.
The reaction equation for the above reaction is shown below:
the invention has the following functions and effects:
the ceftazidime produced by the method has high content and good color grade, the known impurity ceftazidime methyl ester (H) is less than 0.1 percent, and the unknown impurity can be controlled below 0.05 percent; in the method of the invention, the use of methanol is reduced or replaced when synthesizing ceftazidime tert-butyl ester, and the generation of ceftazidime methyl ester is reduced or avoided. And after the reaction is finished, washing and purifying the mixture by water, crystallizing by using a solvent, and washing the mixture by using the solvent during centrifugation to obtain the ceftazidime tert-butyl ester product. The product is used for synthesizing ceftazidime hydrochloride and a pentahydrate of the ceftazidime, and the impurity of ceftazidime methyl ester (H) is obviously reduced by analysis. The reaction conditions in the process are mild and easy to control, the method is suitable for industrial production, the product quality is obviously improved, the market competitiveness of the product is improved, and the safety of the medicine is further guaranteed.
Drawings
FIG. 1, example 1-2 map;
FIG. 2, examples 1-3 map;
FIG. 3, example 2-2 map;
FIG. 4, example 2-3 map;
FIG. 5, example 3-2 map;
FIG. 6, example 3-3 map.
Detailed Description
Examples 1-1,
Adding 520ml of trichloromethane into a clean and dry four-mouth reaction bottle, adding 30ml of tert-butyl alcohol, and cooling to 0-5 ℃. Adding 70g of 7-APCA and 105g of active ester of the tadine, dropwise adding triethylamine at controlled temperature, and adjusting the pH value to 7.0-9.0. Controlling the temperature to be 0-10 ℃ and reacting for 20-24 hours. After the reaction, 150ml of pure water was added, and the mixture was stirred for 1 to 2 hours to separate out chloroform. Dripping isopropanol into the liquid medicine to separate out ceftazidime tert-butyl ester, and stirring at 0-10 ℃ to grow the crystal for 2 hours. And (4) carrying out suction filtration, washing with isopropanol, and drying to obtain a dry ceftazidime tert-butyl ester product.
Weight yield: 145 percent of the purity, 98.9 percent of the purity,
examples 1 to 2,
54ml of formic acid and 36ml of concentrated hydrochloric acid were put into a clean and dry four-neck reaction flask and mixed with stirring. Adding 60g of ceftazidime tert-butyl ester, reacting for 3 hours at 15-20 ℃, and dripping acetone at room temperature until the hydrochloride of the ceftazidime is completely separated out. Growing the crystal for 2 hours at the temperature of 0-10 ℃. And (4) carrying out suction filtration, washing with acetone, and drying to obtain a dry ceftazidime hydrochloride product.
Weight yield: 88 percent, the purity is 99.3 percent and the H content is 0.07 percent.
Examples 1 to 3,
20ml of water for injection and 30ml of acetone are added into a clean and dry four-mouth reaction bottle, and the mixture is stirred and mixed. Adding 50g of ceftazidime hydrochloride, dropwise adding 4N NaOH, and adjusting the pH value to 6.0-6.5 to dissolve and clear. After the solution is clear, 1g of activated carbon is added, and the solution is decolorized for 10 minutes. Filtering, dripping 4M H into the filtrate3PO4Until the crystal is completely precipitated. Stirring at 0-10 deg.C for growing crystal for 1 hr. And (4) carrying out suction filtration, washing with acetone, and drying to obtain a dry ceftazidime pentahydrate product.
Weight yield: 80 percent, the purity is 99.6 percent and the H content is 0.06 percent.
Example 2-1,
300ml of dichloromethane and 13ml of tert-butyl alcohol are added into a clean and dry four-mouth reaction bottle, and the temperature is reduced to 0-5 ℃. Adding 35g of 7-APCA and 50g of active ester of the tadine, dropwise adding triethylamine at controlled temperature, and adjusting the pH value to 7.0-9.0. Controlling the temperature to be 0-10 ℃ and reacting for 20-24 hours. After the reaction, 50ml of pure water was added thereto, and the mixture was stirred for 1 to 2 hours to separate methylene chloride. Dropping acetone into the liquid medicine to separate out ceftazidime tert-butyl ester, and stirring at 0-10 ℃ to grow the crystal for 2 hours. And (4) carrying out suction filtration, washing with acetone, and drying to obtain a dry ceftazidime tert-butyl ester product.
Weight yield: 148 percent, the purity of 98.8 percent,
examples 2-2,
54ml of formic acid and 36ml of concentrated hydrochloric acid were put into a clean and dry four-neck reaction flask and mixed with stirring. Adding 60g of ceftazidime tert-butyl ester, reacting for 3 hours at 15-20 ℃, and dripping acetone at room temperature until the hydrochloride of the ceftazidime is completely separated out. Growing the crystal for 2 hours at the temperature of 0-10 ℃. And (4) carrying out suction filtration, washing with acetone, and drying to obtain a dry ceftazidime hydrochloride product.
Weight yield: 89 percent, the purity is 99.2 percent and the H content is 0.02 percent.
Examples 2 to 3,
20ml of water for injection and 30ml of acetone are added into a clean and dry four-mouth reaction bottle, and the mixture is stirred and mixed. Adding 50g of ceftazidime hydrochloride, dropwise adding 4N NaOH, and adjusting the pH value to 6.0-6.5 to dissolve and clear. After the solution is clear, 1g of activated carbon is added, and the solution is decolorized for 10 minutes. Filtering, dripping 4M H into the filtrate3PO4Until the crystal is completely precipitated. Stirring at 0-10 deg.C for growing crystal for 1 hr. And (4) carrying out suction filtration, washing with acetone, and drying to obtain a dry ceftazidime pentahydrate product.
Weight yield: 83%, purity 99.5% and H0.08%.
Example 3-1,
Adding 500ml of 2-methyltetrahydrofuran into a clean and dry four-mouth reaction bottle, adding 20ml of tert-butyl alcohol/10 ml of methanol, and cooling to 0-5 ℃. Adding 70g of 7-APCA and 105g of active ester of the tadine, dropwise adding DMF at controlled temperature, and adjusting the pH value to 7.0-9.0. Controlling the temperature to be 0-10 ℃ and reacting for 20-24 hours. After the reaction, 200ml of pure water was added and stirred for 1 to 2 hours to separate 2-methyltetrahydrofuran. Dripping isopropanol into the liquid medicine to separate out ceftazidime tert-butyl ester, and stirring at 0-10 ℃ to grow the crystal for 2 hours. And (4) carrying out suction filtration, washing with isopropanol, and drying to obtain a dry ceftazidime tert-butyl ester product.
Weight yield: 143 percent and the purity of 98.6 percent,
examples 3 to 2,
54ml of formic acid and 36ml of concentrated hydrochloric acid were put into a clean and dry four-neck reaction flask and mixed with stirring. Adding 60g of ceftazidime tert-butyl ester, reacting for 3 hours at 15-20 ℃, and dripping acetone at room temperature until the hydrochloride of the ceftazidime is completely separated out. Growing the crystal for 2 hours at the temperature of 0-10 ℃. And (4) carrying out suction filtration, washing with acetone, and drying to obtain a dry ceftazidime hydrochloride product.
Weight yield: 90 percent, the purity is 99.4 percent and the H content is 0.02 percent.
Examples 3 to 3,
20ml of water for injection and 30ml of acetone are added into a clean and dry four-mouth reaction bottle, and the mixture is stirred and mixed. Adding 50g of ceftazidime hydrochloride, dropwise adding 4N NaOH, and adjusting the pH value to 6.0-6.5 to dissolve and clear. After the solution is clear, 1g of activated carbon is added, and the solution is decolorized for 10 minutes. Filtering, dripping 4M H into the filtrate3PO4Until the crystal is completely precipitated. Stirring at 0-10 deg.C for growing crystal for 1 hr. And (4) carrying out suction filtration, washing with acetone, and drying to obtain a dry ceftazidime pentahydrate product.
Weight yield: 81%, purity 99.8% and H0.02%.
Claims (8)
1. A preparation method of ceftazidime tert-butyl ester is characterized by comprising the following steps: taking one or more of dichloromethane, chloroform, tetrahydrofuran, acetonitrile and 2-methyltetrahydrofuran as a main solvent, taking tert-butyl alcohol or a mixed solvent of tert-butyl alcohol and methanol as a cosolvent, carrying out condensation reaction on 7-APCA and the active ester of the tadine under an alkaline condition to generate ceftazidime tert-butyl ester, and after water treatment, carrying out solvent crystallization to obtain the ceftazidime tert-butyl ester;
the using amount of the cosolvent is 10-20% of the total weight of 7-APCA and the active ester of the tadine;
the volume ratio of the main solvent to the cosolvent is 10-25: 1;
when the cosolvent is a mixed solvent of tert-butyl alcohol and methanol, the volume ratio of the tert-butyl alcohol to the methanol is 5-10: 1.
2. The process for the preparation of ceftazidime tert-butyl ester according to claim 1, characterized in that: the molar ratio of the 7-APCA to the active ester of the tadine is 1: 1.05-1.25.
3. The process for the preparation of ceftazidime tert-butyl ester according to claim 1, characterized in that: the molar ratio of the 7-APCA to the active ester of the tadine is 1: 1.15-1.20.
4. The preparation method of ceftazidime tert-butyl ester according to claim 1, characterized in that the specific process steps are as follows:
s1, adding a cosolvent into a main solvent, cooling to 0-10 ℃, adding 7-APCA and a tadine active ester, adjusting the pH value to 7-9, and controlling the temperature to react for 20-24 hours;
and S2, treating the reaction solution with pure water for 1-2 hours, and then carrying out solvent crystallization and washing procedures to obtain ceftazidime tert-butyl ester.
5. The process for the preparation of ceftazidime tert-butyl ester according to claim 4, characterized in that: the reagent for adjusting pH is one or more of triethylamine, diethylamine and ethylenediamine.
6. The process for the preparation of ceftazidime tert-butyl ester according to claim 4, characterized in that: the crystallization solvent and the washing reagent are selected from one or more of pure water, alcohols with carbon number more than 2, ketones and ethers solvents.
7. A preparation method of ceftazidime hydrochloride is characterized by comprising the following steps:
preparing ceftazidime tert-butyl ester according to any one of the methods of claims 1 to 6, adding the ceftazidime tert-butyl ester into a mixed solution of formic acid and hydrochloric acid, reacting for 2 to 5 hours at a reaction temperature of 15 to 20 ℃, and then crystallizing by using an organic reagent to obtain ceftazidime hydrochloride;
wherein the volume ratio of the formic acid to the hydrochloric acid is 1: 0.5-1;
the dosage ratio of the mixed solution of formic acid and hydrochloric acid to the ceftazidime tert-butyl ester is as follows: adding 0.6-1.5 g of ceftazidime tert-butyl ester into each ml of mixed solution of formic acid and hydrochloric acid;
the organic reagent is selected from one or more of alcohols, ketones and ether solvents with the carbon atom number more than 2.
8. A preparation method of ceftazidime pentahydrate is characterized by comprising the following steps:
s1, preparing ceftazidime hydrochloride according to claim 7, and adding the ceftazidime hydrochloride into a mixed solution of water and an organic solvent;
s2, adjusting the pH value to 6.0-6.5 to enable the pH value to be clear;
s3, adding a decoloring agent for decoloring for 5-15 minutes;
and S4, dropwise adding phosphoric acid until crystallization is complete to obtain the ceftazidime pentahydrate.
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| CN102286003A (en) * | 2011-08-05 | 2011-12-21 | 哈药集团制药总厂 | Synthesis method of ceftazidime |
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| CN102286003A (en) * | 2011-08-05 | 2011-12-21 | 哈药集团制药总厂 | Synthesis method of ceftazidime |
| CN102391289A (en) * | 2011-12-03 | 2012-03-28 | 齐鲁安替制药有限公司 | Synthetic methods of ceftazidime intermediate and ceftazidime |
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