CN111039945B - Purification method for protecting meropenem - Google Patents
Purification method for protecting meropenem Download PDFInfo
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- CN111039945B CN111039945B CN201911395649.7A CN201911395649A CN111039945B CN 111039945 B CN111039945 B CN 111039945B CN 201911395649 A CN201911395649 A CN 201911395649A CN 111039945 B CN111039945 B CN 111039945B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/20—Sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/02—Preparation
- C07D477/06—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
Abstract
The invention provides a purification method for protecting meropenem, which comprises the following steps: controlling the temperature to be 10-30 ℃, adding an organic solvent A into the protected meropenem feed liquid, washing an organic phase for three times by using a water phase solvent to obtain the protected meropenem organic phase feed liquid, concentrating the protected meropenem organic phase feed liquid to obtain a concentrated solution, dropwise adding a reverse solvent into the concentrated solution, filtering, washing and drying to obtain the protected meropenem. The invention creatively uses different crystallization solvents to carry out crystallization and purification on the protected meropenem feed liquid to obtain high-purity protected meropenem, thereby preparing the high-purity meropenem. The method disclosed by the invention has the advantages of simplicity in operation, good purification effect and the like, and can be applied to industrial purification and production of meropenem.
Description
Technical Field
The invention relates to a purification method for protecting meropenem, and belongs to the technical field of pharmaceutical chemical synthesis.
Background
Meropenem is the first carbapenem antibiotic capable of being independently used, is the first 1 beta-methyl carbapenem antibiotic, is one of important medicaments for treating severe and multi-drug resistant bacterial infection at present, and is more and more widely applied in clinic. In the prior art, meropenem is generally prepared by reacting a carbapenem bicyclic mother nucleus (a compound shown in formula II) with a meropenem side chain (a compound shown in formula III) to obtain protected meropenem (a compound shown in formula I), and further performing catalytic hydrogenation on the protected meropenem, wherein the reaction route is shown as the following formula:
wherein, the side chain of meropenem is one of the key factors influencing the quality and yield of meropenem. At present, trans-4-hydroxyproline is used as an initial raw material for preparing the meropenem side chain, the amino position of the meropenem side chain is protected, an intermediate or thiolactone with an inverted 4-position configuration is obtained through multi-step reaction, a target side chain is obtained through proper reaction, and the method for obtaining the meropenem key side chain through the reaction of the thiolactone is simple to operate, easily available in raw materials and more in application.
Therefore, the side chain raw material of meropenem prepared by taking thiolactone as an intermediate contains thiolactone intermediate impurities (the compound shown in the formula IV), and the impurities can participate in the subsequent process for preparing the meropenem. In the process of preparing protected meropenem by using the meropenem side chain containing the thiolactone intermediate impurity and the carbapenem bicyclic mother nucleus, the thiolactone intermediate reacts with the protected meropenem further to obtain an impurity V, so that the purity, conversion rate and yield of the protected meropenem are reduced. And (3) carrying out catalytic hydrogenation on the obtained protected meropenem containing the impurity V, removing the protecting group from the protected meropenem to obtain meropenem, and removing the protecting group from the impurity V to obtain an impurity VI, so that the purity and the yield of the meropenem are reduced.
In the prior art, in order to obtain high-purity meropenem, an optimized catalytic hydrogenation process is generally adopted, and a crude meropenem product is recrystallized or a meropenem hydrogenation solution is treated. For example: chinese patent document CN108191869A provides a method for purifying meropenem, which comprises the following steps: s01, preparing a hydrolysate containing meropenem; s02, extracting the hydrogenolysis solution by using a weak polar extractant immiscible with water; s03, separating the water phase in the step (2), and adding a strong polar solvent which is mutually soluble with water to prepare the meropenem crystal. However, impurity VI has a solubility similar to that of meropenem, so that the transferred impurity VI cannot be effectively removed using the above method.
Therefore, there is a need to develop a purification method of protected meropenem, so that high purity protected meropenem as well as meropenem is obtained.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a purification method for protecting meropenem. The method has the advantages of simple operation, good purification effect and the like, can be applied to industrial purification and production of the protected meropenem, the obtained protected meropenem has high purity, and the obtained protected meropenem is further reacted to obtain the high-purity meropenem.
Description of terms:
a compound of formula II: meropenem mother nucleus, chemical name is (4R,5S,6S) -3- (diphenoxy) phosphoryloxy-6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3,2,0] hept-2-ene-2-acid p-nitrobenzyl ester;
a compound of formula III: the meropenem side chain, chemical name is (2S,4S) -2- (dimethylcarbamoyl) -4-mercapto-1- (p-nitrobenzyloxyformyl) -1-pyrrolidine;
a compound of formula IV: thiol lactone intermediate impurities.
The compound numbers in the specification are completely consistent with the structural formula numbers, have the same reference relationship, and are based on the structural formula of the compound.
The technical scheme of the invention is as follows:
a purification method for protecting meropenem comprises the following steps:
controlling the temperature to be 10-30 ℃, adding an organic solvent A into the protected meropenem feed liquid, washing an organic phase for three times by using a water phase solvent to obtain the protected meropenem organic phase feed liquid, concentrating the protected meropenem organic phase feed liquid to obtain a concentrated solution, dropwise adding a reverse solvent into the concentrated solution, filtering, washing and drying to obtain the protected meropenem.
According to the present invention, preferably, the organic solvent a is selected from one of dichloromethane and ethyl acetate; the mass ratio of the organic solvent A to the protective meropenem feed liquid is 1-2: 1.
according to the present invention, preferably, the aqueous phase solvent is selected from one of sodium chloride solution, deionized water, phosphate solution, citrate solution, ammonium chloride solution and acetate solution; the mass ratio of the water phase solvent to the organic solvent A for each washing is 1: 0.7 to 1.5;
more preferably, the mass fraction of the sodium chloride solution is 3-10%;
more preferably, the phosphate is disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate or potassium dihydrogen phosphate, and the mass fraction of the phosphate solution is 3-10%;
preferably, the citrate is monosodium citrate, monopotassium citrate, disodium citrate or dipotassium citrate, and the mass fraction of the citrate solution is 3-10%;
more preferably, the mass fraction of the ammonium chloride solution is 10-37%;
preferably, the acetate is sodium acetate, potassium acetate or ammonium acetate, and the mass fraction of the acetate solution is 3-10%.
According to the invention, preferably, the mass ratio of the concentrated solution to the protective meropenem organic phase feed liquid is 1: 2 to 6.
According to the invention, preferably, the reverse solvent is one or the combination of more than two of methanol, ethanol, deionized water, n-propyl ether, isopropyl ether, methyl tert-butyl ether, n-hexane, cyclohexane, n-heptane, 1-propanol, isopropanol and n-butanol; the mass ratio of the reverse solvent to the organic solvent A is 1: 2.5 to 5.
According to the invention, preferably, the washing is washing with the organic solvent A and the reverse solvent for 1-3 times respectively; the drying is carried out at the temperature of 0-30 ℃ for 5-15 hours.
According to the invention, preferably, the preparation method of the protective meropenem feed liquid comprises the following steps: adding a compound shown in the formula II and a compound shown in the formula III containing impurities IV into an organic solvent B, stirring until the mixture is clear, cooling, adding a catalyst, and carrying out heat preservation reaction to obtain the protected meropenem feed liquid.
According to the present invention, preferably, the organic solvent B is selected from one of N, N-dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile and dichloromethane, and is further preferably N, N-dimethylformamide and dichloromethane; the mass ratio of the organic solvent B to the compound of the formula II is 2-15: 1, and more preferably 4 to 6: 1.
According to the invention, the molar ratio of the compound of formula II to the compound of formula III is preferably 0.9-1.1: 1, more preferably 1: 1.
according to the invention, the mass content of the impurity IV in the compound of the formula III is 0.0006-18%.
According to the invention, preferably, the temperature is reduced to-60-0 ℃; the reaction time is 15-20 hours.
According to the present invention, preferably, the catalyst is selected from one of N, N-diisopropylethylamine, N-methylmorpholine, 2, 6-dimethylpyridine, 2, 4-dimethylpyridine, triethanolamine, 3, 4-dimethylaminopyridine and triethylamine, and is further preferably N, N-diisopropylethylamine; the molar ratio of the catalyst to the compound of the formula II is 1-2: 1.
according to the invention, in the preparation process of the protected meropenem feed liquid, the impurity IV can react with the protected meropenem product to obtain an impurity V, and the impurity V has a structure shown in the following formula. Detecting the content of impurity V in the obtained protected meropenem feed liquid and the obtained protected meropenem by High Performance Liquid Chromatography (HPLC).
The invention also provides a preparation method of the meropenem crude product, which comprises the following steps:
and (3) carrying out catalytic hydrogenation on the obtained protected meropenem to remove a protecting group, so as to obtain a crude meropenem product.
According to the invention, the catalytic hydrogenation for removing the protecting group is the prior art, and the protecting group can be removed by the following method:
adding the obtained protected meropenem, a 4-10% wet palladium-carbon catalyst, 2, 6-dimethylpyridine, tetrahydrofuran and water into a hydrogenation kettle, and sealing a hydrogenation reaction kettle cover. And (3) filling nitrogen into the hydrogenation reaction kettle, boosting the pressure to 0.2-0.3 MPa, opening the kettle for evacuation, releasing the pressure to 0.10-0.15 MPa, closing an evacuation valve, performing nitrogen replacement for 3 times in total according to the method, and performing hydrogen replacement for 3 times according to the nitrogen replacement method after the nitrogen replacement is finished. After the replacement is finished, raising the pressure of hydrogen to 1.5-2.0 MPa, controlling the temperature to be 30-40 ℃, stirring at the speed of 800r/min, and reacting for 2 h. And when the hydrogen pressure is reduced to 1.0-1.2 MPa in the reaction process, replenishing the hydrogen pressure to 1.5-2.0 MPa until the reaction is finished.
And (3) slowly opening an emptying valve of the hydrogenation kettle after the reaction is finished, exhausting hydrogen until the pressure in the reaction kettle is 0MPa, and closing the emptying valve. And (3) filling nitrogen into the hydrogenation reaction kettle, boosting the pressure to 0.2-0.3 MPa, opening the kettle for emptying, releasing the pressure to 0.10-0.15 MPa, closing an emptying valve, performing nitrogen replacement for 3 times in total according to the method, opening the kettle for discharging, and filtering palladium-carbon.
And pouring the hydrogenolysis solution into a separating funnel, standing and layering. And adding the water layer into a five-mouth bottle, controlling the temperature to be 10-15 ℃, adding tetrahydrofuran, separating out crystals when the water solution is turbid, cooling to 5 ℃, growing the crystals for 30min, filtering, and drying for 1 hour at 15-25 ℃ to obtain the white-like meropenem crude product.
According to the invention, in the process of carrying out catalytic hydrogenation on the obtained protected meropenem containing the impurity V, the protecting group of the impurity V is removed to obtain an impurity VI, and the impurity VI has a structure shown in the following formula. The content of impurity VI in the crude meropenem product is detected by High Performance Liquid Chromatography (HPLC).
The invention has the following technical characteristics and beneficial effects:
1. the method for purifying the protected meropenem comprises the steps of firstly adding an organic solvent into the obtained protected meropenem feed liquid, increasing the solubility of the protected meropenem in the feed liquid, preventing the protected meropenem from being separated out, then washing an organic phase with a water phase solvent, removing impurities such as diphenyl phosphate after reaction, obtaining the protected meropenem organic phase feed liquid, concentrating the organic phase feed liquid, then dropwise adding a reverse solvent into the organic phase feed liquid, obtaining the protected meropenem, wherein the reverse solvent can promote the protected meropenem to be separated out, and meanwhile dissolving most of generated impurities V in a mother liquid, and removing the impurities V through filtration. According to the invention, different crystallization solvents are used for carrying out crystallization purification on the protected meropenem feed liquid containing the impurity V, so that the content of the impurity V in the protected meropenem solid can be greatly reduced, and further the content of the impurity VI in the final product meropenem crude product is reduced, thereby preparing high-purity protected meropenem and meropenem raw material medicine.
2. The method has the advantages of simple operation and good purification effect, and can be applied to industrial purification and production of meropenem.
Detailed Description
The present invention is further illustrated by, but not limited to, the following examples.
The raw materials and reagents used in the examples are all commercially available products.
Example 1
A purification method for protecting meropenem comprises the following steps:
(1) adding 99.54g N, N-dimethylformamide and 15g meropenem side chain into a reaction bottle, stirring for dissolving to obtain clear solution, adding 25g meropenem mother nucleus, stirring for clarifying, and cooling to obtain clear solution
Gradually dripping 7.42g N, N-diisopropylethylamine into a reaction bottle at-60 to-50 ℃ after the dripping is finished
And reacting for 18 hours to obtain the protected meropenem feed liquid.
The content of an impurity IV in the meropenem side chain is 6ppm, and the content of an impurity V in the meropenem feed liquid is protected to be 0.03% through High Performance Liquid Chromatography (HPLC) detection.
(2) Adding 265g of dichloromethane into the protected meropenem feed liquid obtained in the step (1) at the temperature of 10-15 ℃, respectively washing an organic phase with 200g of a sodium chloride solution with the mass fraction of 10% for three times to obtain the protected meropenem organic phase feed liquid, concentrating the protected meropenem organic phase feed liquid to obtain 130g of concentrated liquid,
then, 72.5g of isopropyl ether was slowly dropped into the concentrate, the reaction system was filtered, and 26.6g of the obtained solid was used
Dichloromethane was washed 3 times with 7.25g isopropyl ether and dried at 15 c for 12 hours to give protected meropenem.
The content of the impurity V in the meropenem is protected to be 0.02 percent through High Performance Liquid Chromatography (HPLC),
the purity of the protected meropenem is 98.9%, and the yield is 95%.
The obtained protected meropenem is hydrogenated under the action of a catalyst to remove a protecting group, so that a crude meropenem product is obtained, and the specific steps are as follows:
the protected meropenem obtained above, 5g (on a dry basis) of a 10% wet palladium-carbon catalyst, 12g of 2, 6-lutidine, 400mL of tetrahydrofuran and 400mL of water were added to a hydrogenation reactor, and the hydrogenation reactor lid was closed. Charging nitrogen into the hydrogenation reactor, increasing the pressure to 0.2-0.3 MPa, opening the reactor, emptying, releasing the pressure to 0.10-0.15 MPa,
the evacuation valve was closed, and the nitrogen gas was replaced 3 times in total according to the above method, and after completion, hydrogen gas replacement was performed 3 times according to the nitrogen gas replacement method. After the replacement is finished, raising the pressure of hydrogen to 1.5-2.0 MPa, controlling the temperature to be 30-40 ℃, stirring at the speed of 800r/min, and reacting for 2 hours. And when the hydrogen pressure is reduced to 1.0-1.2 MPa in the reaction process, replenishing the hydrogen pressure to 1.5-2.0 MPa until the reaction is finished.
And (3) slowly opening an emptying valve of the hydrogenation kettle after the reaction is finished, exhausting hydrogen until the pressure in the reaction kettle is 0MPa, and closing the emptying valve. And (3) filling nitrogen into the hydrogenation reaction kettle, boosting the pressure to 0.2-0.3 MPa, opening the kettle for emptying, releasing the pressure to 0.10-0.15 MPa, closing an emptying valve, performing nitrogen replacement for 3 times in total according to the method, opening the kettle for discharging, and filtering palladium-carbon.
And pouring the hydrogenolysis solution into a separating funnel, standing and layering. Adding the water layer into a 3000mL five-mouth bottle, controlling the temperature to be 10-15 ℃, adding 1600mL tetrahydrofuran at one time, growing crystals for 30min, controlling the temperature to be 10-15 ℃, then dropwise adding 1000mL tetrahydrofuran, separating out crystals when the water solution is turbid, cooling to 5 ℃, growing crystals for 30min, filtering, and drying at 15-25 ℃ for 1 h to obtain the white-like meropenem crude product.
No impurity vi was detected in the obtained crude meropenem product, the purity of the crude meropenem product was 99.5%, and the yield was 80%.
Example 2
A purification method for protecting meropenem comprises the following steps:
(1) adding 140g of dichloromethane and 15g of meropenem side chain into a reaction bottle, stirring and dissolving to obtain a clear solution, adding 25g of meropenem mother nucleus into the clear solution, stirring the solution until the clear solution is clear, cooling to-25-20 ℃, gradually dropwise adding 7.26g of triethylamine into the reaction bottle, and reacting for 18 hours at-25-20 ℃ after dropwise adding is finished to obtain the protected meropenem feed liquid.
The content of an impurity IV in the side chain of the meropenem is 45 ppm; the content of impurity V in the feed liquid was 0.07% by High Performance Liquid Chromatography (HPLC).
(2) Adding 190g of ethyl acetate into the protected meropenem feed liquid obtained in the step (1) at the temperature of 10-15 ℃, washing an organic phase with 200g of deionized water for three times respectively to obtain the protected meropenem organic phase feed liquid, concentrating the protected meropenem organic phase feed liquid to obtain 150g of concentrated liquid, then slowly dropwise adding 69.2g of n-hexane into the concentrated liquid, filtering a reaction system, washing the obtained solid with 19g of ethyl acetate and 7g of n-hexane for 3 times respectively, and drying at the temperature of 15 ℃ for 8 hours to obtain the protected meropenem.
The content of the impurity V in the protected meropenem is 0.04 percent, the purity of the protected meropenem is 98.5 percent and the yield is 94.5 percent through High Performance Liquid Chromatography (HPLC) detection.
The protected meropenem obtained above is hydrogenated under the action of a catalyst to remove a protecting group, and a crude meropenem product is obtained, and the preparation method is as described in example 1.
The content of the impurity VI in the obtained crude meropenem product is 0.02 percent through High Performance Liquid Chromatography (HPLC), the purity of the crude meropenem product is 99.2 percent, and the yield is 79.8 percent.
Example 3
A purification method for protecting meropenem comprises the following steps:
(1) adding 99.54g N, N-dimethylformamide, 15g of meropenem side chain, 25g of meropenem mother nucleus and 2.6g of impurity IV into a reaction bottle, stirring the solution until the solution is clear, cooling to-10-0 ℃, gradually dropwise adding 7.42g N and N-diisopropylethylamine into the reaction bottle, and reacting for 20 hours at-10-0 ℃ after dropwise adding is finished to obtain the protected meropenem feed liquid.
The content of impurity V in the feed solution was 19.70% as determined by High Performance Liquid Chromatography (HPLC).
(2) Adding 265g of dichloromethane into the protected meropenem feed liquid obtained in the step (1) at the temperature of 10-15 ℃, washing an organic phase three times by using 200g of sodium acetate solution with the mass fraction of 5% respectively to obtain the protected meropenem organic phase feed liquid, concentrating the protected meropenem organic phase feed liquid to obtain 128g of concentrated liquid, then slowly dripping 78.55g of isopropanol into the concentrated liquid, filtering, washing the obtained solid for 3 times by using 26.6g of dichloromethane and 7.86g of isopropanol respectively, and drying for 6 hours at the temperature of 20 ℃ to obtain the protected meropenem.
The content of the impurity V in the protected meropenem is 8.40 percent, the purity of the protected meropenem is 90.8 percent and the yield is 80 percent through High Performance Liquid Chromatography (HPLC) detection.
The protected meropenem obtained above is hydrogenated under the action of a catalyst, a protecting group is removed, and a crude meropenem product is obtained, and the specific preparation method is as described in example 1.
The content of the impurity VI in the obtained crude meropenem product is 1.5 percent through High Performance Liquid Chromatography (HPLC), the purity of the crude meropenem product is 94.6 percent, and the yield is 70 percent.
Comparative example 1
A preparation method of protective meropenem comprises the following steps:
(1) same as in step (1) of example 1.
(2) And slowly dripping 300g of deionized water into the reaction liquid at the temperature of 10-15 ℃, slowly separating out a large amount of white solid, filtering the white solid, washing the obtained solid for 3 times by using 10g N, N-dimethylformamide and 30g of deionized water respectively, and drying for 15 hours at the temperature of 25 ℃ to obtain the protected meropenem.
The content of the impurity V in the protected meropenem is 0.03 percent, the purity of the protected meropenem is 97.7 percent and the yield is 94.8 percent through High Performance Liquid Chromatography (HPLC) detection.
The protected meropenem obtained above is hydrogenated under the action of a catalyst, a protecting group is removed, and a crude meropenem product is obtained, and the specific preparation method is as described in example 1.
The content of the impurity VI in the obtained meropenem crude product is 0.02 percent detected by High Performance Liquid Chromatography (HPLC), which is higher than that of the meropenem crude product in the embodiment 1 of the invention, the purity of the meropenem crude product is 98.6 percent, and the yield is 79.2 percent.
Comparative example 2
A preparation method of protective meropenem comprises the following steps:
(1) same as in step (1) of example 2.
(2) And slowly dropwise adding 300g of deionized water into the reaction liquid at the temperature of 10-15 ℃, slowly separating out a large amount of white solid, filtering the white solid, washing the obtained solid for 3 times by using 14g of dichloromethane and 30g of deionized water respectively, and drying at the temperature of 20 ℃ for 15 hours to obtain the protected meropenem.
The content of the impurity V in the protected meropenem is 0.08 percent detected by High Performance Liquid Chromatography (HPLC), which is higher than that of the impurity V in the embodiment 2 of the invention, the purity of the protected meropenem is 96.1 percent, and the yield is 94.0 percent.
The protected meropenem obtained above is hydrogenated under the action of a catalyst, a protecting group is removed, and a crude meropenem product is obtained, and the specific preparation method is as described in example 1.
The content of the impurity VI in the obtained meropenem crude product is 0.04 percent detected by High Performance Liquid Chromatography (HPLC), which is higher than that of the meropenem crude product in the embodiment 2 of the invention, the purity of the meropenem crude product is 98.3 percent, and the yield is 79 percent.
Comparative example 3
A preparation method of protective meropenem comprises the following steps:
(1) same as in example 3, step (1).
(2) And slowly dripping 300g of deionized water into the reaction liquid at the temperature of 10-15 ℃, slowly separating out a large amount of white solid, filtering the white solid, respectively washing the obtained solid for 3 times by using 10g N, N-dimethylformamide and 30g of deionized water, and drying for 12 hours at the temperature of 25 ℃ to obtain the protected meropenem.
The content of the impurity V in the protected meropenem is 15.0 percent detected by High Performance Liquid Chromatography (HPLC), which is higher than that of the impurity V in the embodiment 3 of the invention, the purity of the protected meropenem is 80 percent, and the yield is 75 percent.
The protected meropenem obtained above is hydrogenated under the action of a catalyst, a protecting group is removed, and a crude meropenem product is obtained, and the specific preparation method is as described in example 1.
The content of impurity VI in the crude meropenem product obtained by High Performance Liquid Chromatography (HPLC) is 3.8 percent, which is higher than that of the crude meropenem product obtained in the embodiment 3 of the invention, the purity of the crude meropenem product is 79 percent, and the yield is 50 percent.
The purification method can effectively reduce the content of the impurity V in the protected meropenem, so that the content of the impurity VI in the crude meropenem product is reduced, and the protected meropenem and the meropenem with higher purity are obtained.
Claims (8)
1. A purification method for protecting meropenem comprises the following steps:
adding a compound of a formula II and a compound of a formula III containing impurities IV into an organic solvent B, stirring until the mixture is clear, cooling, adding a catalyst, and carrying out heat preservation reaction to obtain protected meropenem feed liquid;
controlling the temperature to be 10-30 ℃, adding an organic solvent A into the protected meropenem feed liquid, washing an organic phase for three times by using a water phase solvent to obtain the protected meropenem organic phase feed liquid, concentrating the protected meropenem organic phase feed liquid to obtain a concentrated solution, dropwise adding a reverse solvent into the concentrated solution, filtering, washing and drying to obtain the protected meropenem;
the reverse solvent is one or the combination of more than two of methanol, ethanol, deionized water, n-propyl ether, isopropyl ether, methyl tert-butyl ether, 1-propanol, isopropanol and n-butanol; the mass ratio of the reverse solvent to the organic solvent A is 1: 2.5 to 5.
2. The process for purifying protected meropenem of claim 1, wherein the organic solvent A is selected from the group consisting of dichloromethane and ethyl acetate; the mass ratio of the organic solvent A to the protective meropenem feed liquid is 1-2: 1.
3. the process for the purification of protected meropenem of claim 1, wherein the aqueous solvent is selected from the group consisting of sodium chloride solution, deionized water, phosphate solution, citrate solution, ammonium chloride solution, acetate solution; the mass ratio of the water phase solvent to the organic solvent A for each washing is 1: 0.7 to 1.5.
4. The purification method of protected meropenem according to claim 3, wherein the sodium chloride solution is present in an amount of 3-10% by weight; the phosphate is disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate or potassium dihydrogen phosphate, and the mass fraction of the phosphate solution is 3-10%; the citrate is monosodium citrate, monopotassium citrate, disodium citrate or dipotassium citrate, and the mass fraction of the citrate solution is 3-10%; the mass fraction of the ammonium chloride solution is 10-37%; the acetate is sodium acetate, potassium acetate or ammonium acetate, and the mass fraction of the acetate solution is 3-10%.
5. The method for purifying protected meropenem according to claim 1, wherein the mass ratio of the concentrated solution to the protected meropenem organic phase feed solution is 1: 2 to 6.
6. The method for purifying protected meropenem according to claim 1, wherein the washing is carried out 1 to 3 times with the organic solvent A and the counter solvent, respectively.
7. The method for purifying protected meropenem according to claim 1, wherein the drying is carried out at 0-30 ℃ for 5-15 hours.
8. The process for the purification of protected meropenem of claim 1, wherein the organic solvent B is N, N-dimethylformamide; the mass ratio of the organic solvent B to the compound of the formula II is 2-15: 1;
the molar ratio of the compound shown in the formula II to the compound shown in the formula III is 0.9-1.1: 1;
the temperature is reduced to minus 60-0 ℃; the reaction time is 15-20 hours;
the catalyst is selected from one of N, N-diisopropylethylamine, N-methylmorpholine, 2, 6-dimethylpyridine, 2, 4-dimethylpyridine, triethanolamine, 3, 4-dimethylaminopyridine and triethylamine; the molar ratio of the catalyst to the compound of the formula II is 1-2: 1.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911395649.7A CN111039945B (en) | 2019-12-30 | 2019-12-30 | Purification method for protecting meropenem |
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