CN110698479A - Synthetic method of ertapenem monosodium salt - Google Patents
Synthetic method of ertapenem monosodium salt Download PDFInfo
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- CN110698479A CN110698479A CN201810747155.XA CN201810747155A CN110698479A CN 110698479 A CN110698479 A CN 110698479A CN 201810747155 A CN201810747155 A CN 201810747155A CN 110698479 A CN110698479 A CN 110698479A
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- ertapenem
- monosodium salt
- synthesis method
- lower alcohol
- ertapenem monosodium
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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
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a purification method of ertapenem sodium salt. Which comprises the following steps: dissolving the ertapenem crude product in purified water, adjusting the pH value to 8.0-10.0, adding a lower alcohol dropwise, filtering to remove impurities, adjusting the pH value of the filtrate to 5.8-6.5, and adding lower alcohol dropwise for crystallization to obtain the ertapenem refined product. The method can effectively remove ring-opening impurities and polymers existing in ertapenem, obviously improve the color of the product and obviously improve the purity. The method has high yield and convenient operation, and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, and in particular relates to a method for purifying ertapenem monosodium salt.
Background
Ertapenem sodium (ertapenem sodium) is a new broad-spectrum carbapenem antibiotic developed by merck pharmaceutical company in the united states and has the chemical name: [4R,5S,6S ] -3- [ [ (3S,5S) -5- [ [ (3-carboxyphenyl) amino ] -3-pyrrolidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid monosodium salt. The product has strong antibacterial activity and wide antibacterial spectrum, and is a first-line treatment selection medicament for deep infection symptoms such as acute pelvic inflammatory disease, complicated urethral infection and the like.
At present, several companies in China have devoted to the research and development of ertapenem, and two main synthesis methods exist. One is the first generation preparation method of Merck, which obtains ertapenem through deprotection of a double-protected intermediate (WO2013121279, US20110288290, US20090312539, etc.); the other method is as follows: the ertapenem (WO201238979, CN201010188533) is obtained after deprotection of a single-protection intermediate, but Pd/C is adopted as a catalyst in the two methods, so that the cost is high, and the yield is low.
Disclosure of Invention
The invention aims to overcome the defect of high ertapenem cost in the prior art and provide a method for purifying ertapenem sodium salt. The specific synthetic route is as follows:
the synthetic route comprises the following steps:
dissolving ertapenem crude product in purified water, adjusting the pH of a system to be alkaline, and generating ertapenem disodium salt, wherein the system is a clear water solution;
and
step (2) adding lower alcohol dropwise into the ertapenem disodium salt, and filtering to remove impurities when turbidity occurs in the system; adjusting the pH of the filtrate to be weakly acidic, continuously dropwise adding lower alcohol for crystallization, and filtering to obtain ertapenem monosodium salt by refining, wherein the ertapenem monosodium salt is prepared by the following steps: [4R,5S,6S ] -3- [ [ (3S,5S) -5- [ [ (3-carboxyphenyl) amino ] -3-pyrrolidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid monosodium salt.
Preferably, the alkali in the step (1) is at least one of sodium hydroxide, sodium methoxide, sodium carbonate and sodium bicarbonate.
Preferably, the pH value in the step (1) is 8.0-10.0.
Preferably, the lower alcohol in step (2) is at least one of methanol, ethanol, isopropanol and n-propanol.
Preferably, the crystallization temperature in the step (2) is-30 to-10 ℃.
Preferably, the pH value in the step (2) is 5.8-6.5.
The ertapenem monosodium salt synthesized by the preparation method has the advantages of obviously improved purity, reduced cost and simplified operation steps.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Furthermore, it should be understood that various changes or modifications can be made by those skilled in the art after reading the description of the present invention, and such equivalents also fall within the scope of the invention.
Example 1
Dissolving the ertapenem crude product in purified water, adding sodium hydroxide into the system, adjusting the pH of the water phase to 8.5, and converting the ertapenem into a clear aqueous solution of disodium salt. Under the condition of minus 30 ℃, methanol is dripped into the aqueous phase of ertapenem disodium salt until the system is turbid, the mixture is filtered, the pH value of the filtrate is adjusted to be 6.0, then ethanol is dripped into the filtrate until a large amount of solid is obtained, and the filtered filter cake is refined to obtain ertapenem monosodium salt, namely [4R,5S,6S ] -3- [ [ (3S,5S) -5- [ [ (3-carboxyphenyl) amino ] -3-pyrrolidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid monosodium salt, wherein the yield is 85.6%.
Example 2
Dissolving the ertapenem crude product in purified water, adding sodium methoxide into the system, adjusting the pH of the water phase to 10.0, and converting the ertapenem into a clear water solution of disodium salt. Under the condition of-20 ℃, methanol is dropwise added into an ertapenem disodium salt water phase until the system is turbid, the mixture is filtered, the pH value of the filtrate is adjusted to be 6.5, then n-propanol alcohol is dropwise added into the filtrate until a large amount of solid is obtained, and the filtered filter cake is refined to obtain ertapenem monosodium salt, namely [4R,5S,6S ] -3- [ [ (3S,5S) -5- [ [ (3-carboxyphenyl) amino ] -3-pyrrolidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid monosodium salt, wherein the yield is 82.4%.
Example 3
Dissolving the ertapenem crude product in purified water, adding sodium carbonate into the system, adjusting the pH of the water phase to 8.0, and converting the ertapenem into a clear aqueous solution of disodium salt. Under the condition of-10 ℃, methanol is dropwise added into an ertapenem disodium salt water phase until the system is turbid, the mixture is filtered, the pH value of the filtrate is adjusted to be 5.8, n-propanol alcohol is dropwise added into the filtrate until a large amount of solid is obtained, and the filtered filter cake is refined to obtain ertapenem monosodium salt, namely [4R,5S,6S ] -3- [ [ (3S,5S) -5- [ [ (3-carboxyphenyl) amino ] -3-pyrrolidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid monosodium salt, wherein the yield is 79.8%.
Example 4 product identification and quality study test
Example 4 product identification and quality study test
1g of the sample in example 1 was sampled, and white to off-white crystalline powder was observed.
The content of the sample is measured by chromatography, and the retention time of the main peak of the sample is consistent with that of the main peak of ertapenem sodium salt serving as a reference substance.
Taking a small amount of sample, and adding water to prepare a solution with the pH value of 5.7-6.8 of 0.1 g/mL.
Other impurity content test shows that the content of oxazinone is less than or equal to 0.5%, the content of ring-opening degradation product is less than or equal to 0.5%, the content of Pro-MABA is less than or equal to 0.4%, except all specific impurities (oxazinone, Pro-MABA, ring-opening degradation product, dimer I + II, dimer VI, dimer III, hydrated dimer (a + b), and dimer V), any degradation impurity is less than or equal to 0.1%, the total content of dimer is less than or equal to 1.2%, and the total content of impurity is less than or equal to 2.0%.
The sample was tested by high performance liquid chromatography and had a purity of between 98.1% and 98.7%.
According to the experimental data, the ertapenem sodium salt prepared by the preparation method disclosed by the invention is high in yield and purity, and is suitable for industrial production.
Claims (6)
1. A method for purifying ertapenem monosodium salt, the synthetic route is
The synthesis method comprises the following synthesis steps:
step (1): dissolving ertapenem crude product in purified water, adjusting the pH of the system to be alkaline, and generating ertapenem disodium salt, wherein the system is a clear aqueous solution;
step (2): adding lower alcohol dropwise into the ertapenem disodium salt, and filtering to remove impurities when turbidity appears in the system; adjusting the pH of the filtrate to be weakly acidic, continuously dropwise adding lower alcohol for crystallization, and filtering to obtain ertapenem monosodium salt by refining, wherein the ertapenem monosodium salt is prepared by the following steps: [4R,5S,6S ] -3- [ [ (3S,5S) -5- [ [ (3-carboxyphenyl) amino ] -3-pyrrolidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid monosodium salt.
2. The synthesis method of ertapenem monosodium salt according to claim 1 wherein the base in step (1) is at least one of sodium hydroxide, sodium methoxide, sodium carbonate, sodium bicarbonate.
3. The synthesis method of ertapenem monosodium salt according to claim 1, characterized in that the pH in step (1) is 8.0-10.0.
4. The synthesis method of ertapenem monosodium salt as claimed in claim 1, characterized in that the lower alcohol in step (2) is at least one of methanol, ethanol, isopropanol, n-propanol.
5. The synthesis method of ertapenem monosodium salt according to claim 1 characterized in that the crystallization temperature in step (2) is-30 to-10 ℃.
6. The synthesis method of ertapenem monosodium salt according to claim 1 wherein the pH in step (2) is 5.8-6.5.
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| CN201810747155.XA CN110698479A (en) | 2018-07-09 | 2018-07-09 | Synthetic method of ertapenem monosodium salt |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102363617A (en) * | 2011-11-09 | 2012-02-29 | 上海希迈医药科技有限公司 | Ertapenem monosodium salt crystal and preparation method thereof |
| CN103159770A (en) * | 2013-03-22 | 2013-06-19 | 成都自豪药业有限公司 | Crystal form of ertapenem monosodium salt |
| WO2013121279A2 (en) * | 2012-02-14 | 2013-08-22 | Aurobindo Pharma Limited | Process to prepare ertapenem |
| CN104130262A (en) * | 2014-08-12 | 2014-11-05 | 湖南凯米尔生物科技有限公司 | Ertapenem and ertapenem side chain, as well as preparation methods of ertapenem and ertapenem side chains |
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- 2018-07-09 CN CN201810747155.XA patent/CN110698479A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102363617A (en) * | 2011-11-09 | 2012-02-29 | 上海希迈医药科技有限公司 | Ertapenem monosodium salt crystal and preparation method thereof |
| WO2013121279A2 (en) * | 2012-02-14 | 2013-08-22 | Aurobindo Pharma Limited | Process to prepare ertapenem |
| CN103159770A (en) * | 2013-03-22 | 2013-06-19 | 成都自豪药业有限公司 | Crystal form of ertapenem monosodium salt |
| CN104130262A (en) * | 2014-08-12 | 2014-11-05 | 湖南凯米尔生物科技有限公司 | Ertapenem and ertapenem side chain, as well as preparation methods of ertapenem and ertapenem side chains |
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Application publication date: 20200117 |