CN114105988B - Synthetic method of ertapenem sodium - Google Patents
Synthetic method of ertapenem sodium Download PDFInfo
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- CN114105988B CN114105988B CN202210076557.8A CN202210076557A CN114105988B CN 114105988 B CN114105988 B CN 114105988B CN 202210076557 A CN202210076557 A CN 202210076557A CN 114105988 B CN114105988 B CN 114105988B
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- 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
- C07D477/08—Modification of a carboxyl group directly attached in position 2, e.g. esterification
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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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Abstract
The application belongs to the technical field of drug synthesis, and particularly relates to a synthetic method of ertapenem sodium. The application provides a synthesis method of ertapenem sodium, which comprises the following steps: under the conditions of alkali, catalyst and hydrogen atmosphere, mixing a compound shown in a formula 1 with a mixed solvent for hydrogenation reaction, filtering to obtain a product solution, extracting and purifying ethyl acetate, and adjusting the pH value of a water phase to 4-7 to obtain an acidic product solution; adding a crystallization solvent into the acidic product solution for crystallization to obtain ertapenem sodium; the ertapenem sodium has a structure shown in formula 2. The application provides a synthesis method of ertapenem sodium, which effectively solves the technical problems of complex post-treatment, low yield, high heavy metal residue in products and poor purity of the existing ertapenem synthesis method.
Description
Technical Field
The application belongs to the technical field of drug synthesis, and particularly relates to a synthetic method of ertapenem sodium.
Background
Ertapenem (Ertapaem, structure formula is
) Is a carbapenem antibiotic with broad-spectrum antibacterial property, is developed by merck company and astrazen company, and has the chemical name of (4R, 5R, 6S) -6- [ (3S,5S) -5- [ (3-carboxyphenyl) carbamoyl]Pyrrolidin-3-yl radical]Sulfur-6- [ (1R) -1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0]Hept-2-ene-2-carboxylic acid.
The current main method for industrially producing the penem compounds comprises the following steps: palladium-carbon hydrogenation is adopted and then deprotection is carried out, and ertapenem is also subjected to hydrogenation deprotection in the mode. However, the deprotection method faces the problem that heavy metals exceed the standard, and the product is seriously degraded due to the instability of ertapenem and the complicated post-treatment operation.
In conclusion, the traditional ertapenem synthesis method needs complicated post-treatment and purification treatment, and the obtained final product still has the problem of high heavy metal content.
Disclosure of Invention
In view of the above, the application provides a synthesis method of ertapenem sodium, which effectively solves the technical problems of the existing ertapenem synthesis method that complicated post-treatment is required, the yield is low, the heavy metal residue in the product is high, and the purity is poor.
The application provides a synthesis method of ertapenem sodium, which comprises the following steps:
under the conditions of alkali, catalyst and hydrogen atmosphere, mixing a compound shown in a formula 1 with a mixed solvent for hydrogenation reaction, filtering to obtain a product solution, extracting and purifying ethyl acetate, and adjusting the pH value of a water phase to 4-7 to obtain an acidic product solution; adding a crystallization solvent into the acidic product solution for crystallization to obtain ertapenem sodium; the ertapenem sodium has a structure shown in formula 2;
Specifically, ertapenem sodium is obtained by drying after crystallization.
In some embodiments, the pH of the product solution is adjusted to 5.5 to 6.
In another embodiment, the mixed solvent includes water, methanol, n-propanol, and ethyl acetate.
In another embodiment, the mass ratio of the water, the methanol, the n-propanol, the ethyl acetate and the compound shown in the formula 1 is (1-15): 1-10: (1-15): 1.
In some embodiments, the mass ratio of the water, the methanol, the n-propanol, the ethyl acetate and the compound represented by the formula 1 is (3-10): 3-8): 2-8): 4-12): 1.
In another embodiment, the base is selected from an organic base or/and an inorganic base; the dosage of the alkali is 1-10 molar equivalents of the compound shown in the formula 1;
the organic base is selected from one or more of diisopropylethylamine, diisopropylamine, tetramethylguanidine, triethylamine, diethylamine, 4-dimethylaminopyridine and 2, 6-dimethylpyridine; the inorganic base is selected from one or more of sodium carbonate, sodium bicarbonate and disodium hydrogen phosphate.
In some embodiments, the base is used in an amount of 2 to 5 molar equivalents of the compound of formula 1.
In another embodiment, the catalyst is selected from one or both of palladium on carbon and tetrakis (triphenylphosphine) palladium; the dosage of the catalyst is 5-50% of the mass of the compound shown in the formula 1.
In some embodiments, the catalyst is used in an amount of 8% to 20% by mass of the total mass of the compound represented by formula 1, and more specifically, the catalyst is palladium on carbon, which is commercially available palladium on carbon having a palladium content of 7.5%.
In another embodiment, the pressure of the hydrogen is 0.5-3 MPa.
In some embodiments, the pressure of the hydrogen gas is 1.0-2.0 MPa.
In another embodiment, the temperature of the hydrogenation reaction is 0-30 ℃; the time of the hydrogenation reaction is 60 min-240 min.
In some embodiments, the temperature of the hydrogenation reaction is 5 to 20 ℃.
In another embodiment, the crystallization solvent is selected from one or more of methanol, n-propanol, isopropanol, and ethanol.
Specifically, the crystallization solvent is a mixed solution of methanol and n-propanol with equal volume.
In another embodiment, acid liquor is adopted to adjust the pH value of the product solution after the ethyl acetate extraction and purification; the acid is selected from one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, formic acid, citric acid and tartaric acid.
In some embodiments, the acid is selected from hydrochloric acid or/and acetic acid.
In another embodiment, the preparation method of the compound represented by formula 1 comprises:
mixing a compound shown as a formula 3 and a compound shown as a formula 4 in a solvent, and carrying out condensation reaction under the action of alkali; then adding phosphoric acid, and finally carrying out crystallization to obtain a compound shown in a formula 1;
Specifically, by adopting the synthesis method, the purity of the prepared ertapenem sodium is more than 98%, and the heavy metal residue of the ertapenem sodium is less than 10 ppm.
The application provides a method for preparing ertapenem sodium, which comprises the following synthetic route that a compound shown in formula 1 is used as a main starting material of ertapenem sodium, a mixed solvent system containing water, methanol, n-propanol and ethyl acetate is used for hydrogenation reaction, liquid separation is directly carried out after the reaction is finished and filtration is carried out, a product solution is obtained, the pH value of the product solution is adjusted to 4-7, and finally, crystallization solvents (such as methanol and n-propanol) are directly adopted for crystallization, so that the ertapenem sodium with high purity and low heavy metal content can be obtained. The innovation points of the application are as follows: (1) the compound shown in the formula 1 is subjected to hydrogenation reaction, so that the obtained ertapenem sodium has higher purity; (2) methanol and n-propanol are used as crystallization solvents, so that the introduction of various solvents is avoided; (3) methanol and n-propanol in the hydrogenation system are helpful for dissolving the compound shown in the formula 1 to form a homogeneous phase system, the reaction is easy to control and thorough, and meanwhile, the reaction concentration can be reduced, and the generation of dimers is reduced; (4) after the reaction of the ethyl acetate in the mixed solvent system is finished, the ethyl acetate is filtered and then is subjected to liquid separation, so that the purification effect can be achieved, column-passing purification is not needed, and complicated operation is avoided; (5) the ertapenem sodium crystallized in a mixed solvent system of water-methanol-n-propanol-ethyl acetate has high purity, low heavy metal content, high yield, simple post-treatment operation and is more beneficial to large-scale industrial production.
Drawings
In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.
Figure 1 is a chromatogram of ertapenem sodium provided in the examples of the present application.
Detailed Description
The application provides a synthesis method of ertapenem sodium, which is used for solving the technical defects that in the synthesis method of ertapenem in the prior art, complicated post-treatment is required, the yield is low, the heavy metal residue of a product is high, and the purity is poor.
The technical solutions in the embodiments of the present application will be described clearly and completely below, and it should be understood that the described embodiments are only a part of the embodiments of the present application, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.
The raw materials and reagents used in the following examples are commercially available or self-made.
Carbapenem parent nucleus MAP in the following examples has a structure represented by formula 3; ertapenem side chain hydrochloride has the structure shown in formula 4.
Palladium on carbon used in the following examples: palladium on carbon with a palladium content of 7.5% is commercially available.
Example 1
The embodiment of the application provides a preparation method of a compound shown in a formula 1, which specifically comprises the following steps:
according to the following synthetic route, 94.2g of carbapenem parent nucleus MAP and 57.3g of ertapenem side chain hydrochloride are dissolved in 600g of DMF, 60.8g of tetramethylguanidine is added dropwise at-50 ℃, stirring is carried out for condensation reaction, after the reaction is finished, the pH value of phosphoric acid is adjusted to 5, and the feed liquid after the acid adjustment is added into water for crystallization to obtain the solid compound shown in formula 1. The purity thereof is 98.9%.
Example 2
The embodiment of the application provides a preparation method of ertapenem sodium, which specifically comprises the following steps:
adding 93g of water, 50g of methanol, 24g of n-propanol, 53g of ethyl acetate, 10g of the compound shown in the formula 1 and 4.2g of sodium bicarbonate into a three-neck flask, stirring for dissolving, adding into a hydrogenation kettle, simultaneously adding 1.13g of palladium carbon, replacing with nitrogen, adding hydrogen gas to 2.0Mpa, reacting at 20 ℃ for 3 hours, filtering after the reaction is finished, separating liquid to obtain a product solution, adjusting the pH value of the product solution to 6.0 by using aqueous hydrochloric acid, adding isometric methanol and n-propanol for crystallization, and drying to obtain 6.7g of white ertapenem sodium solid, wherein the molar yield is 82.1%, the HPLC purity is 99.09% and the heavy metal content is less than 10 ppm.
The results of the chromatography of ertapenem sodium prepared in the examples of the present application are shown in table 1 and fig. 1, and ertapenem sodium with a heavy metal content of <10ppm was prepared in the present application.
TABLE 1
Comparative example 1
The application provides a conventional method for preparing ertapenem sodium, which specifically comprises the following steps:
1. introducing nitrogen into 500ml four-neck bottle, adding 100 ml Dimethylformamide (DMF), cooling to 0 deg.C, adding 11.6 g MAP (MAP is compound shown in formula 3), and adding 6.48 g side chain ES (chemical structural formula is shown in formula
) 0.3 g of tri-N-butylphosphine is added dropwise, after stirring and complete dissolution, the temperature is reduced to minus 50 ℃, 8.1 g of Tetramethylguanidine (TMG) is added dropwise, 0.35 g of 4-N, N-Dimethylaminopyridine (DMAP) is added dropwise, the system temperature is kept at minus 50 ℃, and the reaction is carried out for 3 hours. After the reaction, 20mL of saturated KH was added dropwise2PO4Adjusting the pH value of the aqueous solution to 7, stirring the aqueous solution for 30min at about minus 40 ℃, and heating the aqueous solution to 10 ℃. Slowly dripping the reaction solution into 1000mL of 1% hydrochloric acid solution to ensure that the pH is 5.5, stirring for 30min after the addition is finished, performing suction filtration, and washing twice with ice water to obtain an ertapenem intermediate (the chemical structural formula is shown in the specification) with a single protection structure
) The purity is 94.8%.
2. The ertapenem sodium is prepared by catalytically hydrogenating the ertapenem intermediate with a single protection structure in the step 1, and the specific method comprises the following steps:
2.1, 7g of palladium on carbon (commercially available palladium on carbon having a palladium content of 7.5%) was added to 80ml of pure water and stirred uniformly to obtain solution A.
2.2 dissolving the ertapenem intermediate of the uniprotection structure obtained in step 1 without drying in 210ml Tetrahydrofuran (THF), after complete dissolution, adding to 60ml water (containing NaHCO)3And the molar ratio to MAP was 3 equivalents), to obtain solution B.
And 2.3, adding the solution B into the solution A to perform hydrogenation reaction, wherein the hydrogenation temperature is 20 ℃, the pressure of hydrogen is 1.7Mpa, and the hydrogenation time is 90 min.
2.4, post-treatment: the hydrogenated liquid is decanted, the pH is adjusted to 5.8 with 20% hydrochloric acid, filtration is carried out, and the filtrate is treated with 300mL of cold CH2Cl2Extracting once, separating out organic phase, filtering water layer, adding 3g of activated carbon, stirring for 10min, and performing suction filtration to obtain solution C.
2.5, dropwise adding 250mL of methanol into the solution C, then dropwise adding 250mL of isopropanol, cooling to-10 ℃, stirring for 30min, then cooling to-15 ℃, dropwise adding 500mL of methanol/isopropanol (1: 1) mixed solution, stirring for 30min, leaching a filter cake with acetone, and drying in vacuum to obtain 4.2g of light yellow ertapenem sodium, wherein the yield is 43.3%, and the purity is 96.1%.
The stability of the compound of formula 1 of example 1 and the ertapenem intermediate of single protection structure of comparative example 1 were determined and the results are shown in table 2.
The purity and yield of ertapenem sodium prepared in example 2 and ertapenem sodium prepared in comparative example 1 were determined and the results are shown in table 3.
TABLE 2
TABLE 3
In summary, in the method for preparing ertapenem sodium by using the compound shown in formula 1 provided in the embodiment of the present application, the obtained ertapenem sodium has higher purity and yield, because the adopted compound shown in formula 1 has higher stability, less degradation is caused during the hydrogenation deprotection process, and the yield and purity of the hydrogenation product are better.
The foregoing is only a preferred embodiment of the present application and it should be noted that those skilled in the art can make several improvements and modifications without departing from the principle of the present application, and these improvements and modifications should also be considered as the protection scope of the present application.
Claims (6)
1. A synthetic method of ertapenem sodium is characterized by comprising the following steps:
under the conditions of alkali, catalyst and hydrogen atmosphere, mixing a compound shown in a formula 1 with a mixed solvent for hydrogenation reaction, filtering to obtain a product solution, extracting and purifying ethyl acetate, and adjusting the pH value of a water phase to 4-7 to obtain an acidic product solution; adding a crystallization solvent into the acidic product solution for crystallization to obtain ertapenem sodium; the ertapenem sodium has a structure shown in formula 2; the mixed solvent comprises water, methanol, n-propanol and ethyl acetate; the base is selected from inorganic bases; the dosage of the alkali is 1-10 molar equivalents of the compound shown in the formula 1;
the inorganic base is selected from one or more of sodium carbonate, sodium bicarbonate and disodium hydrogen phosphate; the catalyst is selected from one or two of palladium carbon and tetrakis (triphenylphosphine) palladium; the dosage of the catalyst is 5-50% of the total mass of the compound shown in the formula 1; the crystallization solvent is selected from one or more of methanol, n-propanol, isopropanol and ethanol;
2. The synthesis method of claim 1, wherein the mass ratio of the water, the methanol, the n-propanol, the ethyl acetate and the compound represented by the formula 1 is (1-15): 1-10: (1-15): 1.
3. The synthesis method according to claim 1, wherein the pressure of the hydrogen gas is 0.5-3 Mpa.
4. The synthesis method according to claim 1, wherein the temperature of the hydrogenation reaction is 0-30 ℃; the time of the hydrogenation reaction is 60 min-240 min.
5. The synthesis method according to claim 1, characterized in that the pH value of the product solution is adjusted with an acid solution; the acid is selected from one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, formic acid, citric acid and tartaric acid.
6. The method for synthesizing the compound of claim 1, wherein the method for preparing the compound of formula 1 comprises the following steps:
mixing a compound shown as a formula 3 and a compound shown as a formula 4 in a solvent, and carrying out condensation reaction under the action of alkali; then adding phosphoric acid, and finally carrying out crystallization to obtain a compound shown in a formula 1;
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| CN202210076557.8A CN114105988B (en) | 2022-01-24 | 2022-01-24 | Synthetic method of ertapenem sodium |
| PCT/CN2022/143602 WO2023138341A1 (en) | 2022-01-24 | 2022-12-29 | Synthesis method for ertapenem sodium |
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| CN102690266A (en) * | 2011-09-02 | 2012-09-26 | 深圳市海滨制药有限公司 | Method for preparing ertapenem sodium |
| WO2013121279A2 (en) * | 2012-02-14 | 2013-08-22 | Aurobindo Pharma Limited | Process to prepare ertapenem |
| CN106279175A (en) * | 2016-08-12 | 2017-01-04 | 上海龙翔生物医药开发有限公司 | A kind of preparation method of Ertapenem Sodium |
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| AU749234B2 (en) * | 1998-03-02 | 2002-06-20 | Merck Sharp & Dohme Corp. | Process for synthesizing carbapenem antibiotics |
| WO2012038979A2 (en) * | 2010-09-24 | 2012-03-29 | Sequent Anti Biotics Private Limited | A process for preparation of ertapenem |
| CN102731506B (en) * | 2011-04-13 | 2015-08-12 | 石药集团中奇制药技术（石家庄）有限公司 | The preparation method of a kind of ertapenem and sodium salt thereof |
| IN2013MU03862A (en) * | 2013-12-11 | 2015-07-31 | Unimark Remedies Ltd | |
| CN114105988B (en) * | 2022-01-24 | 2022-04-29 | 深圳市海滨制药有限公司 | Synthetic method of ertapenem sodium |
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|---|---|---|---|---|
| CN102690266A (en) * | 2011-09-02 | 2012-09-26 | 深圳市海滨制药有限公司 | Method for preparing ertapenem sodium |
| WO2013121279A2 (en) * | 2012-02-14 | 2013-08-22 | Aurobindo Pharma Limited | Process to prepare ertapenem |
| CN106279175A (en) * | 2016-08-12 | 2017-01-04 | 上海龙翔生物医药开发有限公司 | A kind of preparation method of Ertapenem Sodium |
Non-Patent Citations (2)
| Title |
|---|
| Practical Synthesis of the New Carbapenem Antibiotic Ertapenem Sodium;J. Michael Williams，等;《J. Org. Chem.》;20050813;第7479-7487页 * |
| 厄他培南钠的合成研究;刘建红，等;《精细化工中间体》;20190630;第25-27，30页 * |
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| WO2023138341A9 (en) | 2023-09-14 |
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