CN111560028A - New indication of cefepime hydrochloride medicinal preparation for treating otitis media - Google Patents
New indication of cefepime hydrochloride medicinal preparation for treating otitis media Download PDFInfo
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- CN111560028A CN111560028A CN202010336050.2A CN202010336050A CN111560028A CN 111560028 A CN111560028 A CN 111560028A CN 202010336050 A CN202010336050 A CN 202010336050A CN 111560028 A CN111560028 A CN 111560028A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
- C07D501/46—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by carboxylic acids containing hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
Abstract
The invention relates to the technical field of medicine preparation, and discloses cefepime hydrochloride, a preparation method and a new indication for treating otitis media. The cefepime hydrochloride provided by the specific preparation method disclosed by the invention is low in impurity content, high in stability and remarkable in drug effect, the quality of a preparation product is improved, the safety and the effectiveness of the preparation product are favorably ensured, and the cefepime hydrochloride has an application in preparing a drug for treating otitis media.
Description
Technical Field
The invention relates to a medicine preparation technology, and in particular relates to a cefepime hydrochloride composition, a preparation method and application thereof.
Background
Cefepime hydrochloride, english name: CEFEPIME HYDROCHLORIDE, marketed in 1997 by the company Bristol-Myers Squibb, is a fourth generation cephalosporin antibiotic whose antibacterial action mechanism is to affect the synthesis of bacterial cell walls. Similar to other cephalosporins, it can inhibit transpeptidation of transpeptidase in the last step of cell wall synthesis, so that cross-link cannot be formed, thereby affecting cell wall synthesis and leading to bacterial lysis and death.
The chemical name of cefepime hydrochloride is 1- [ [ (6R, 7R) -7- [ (2Z) - (2-amino-4-thiazolyl) (methoxyimino) acetamido)]-2-carboxy-8-oxo-5-thia-1-azabicyclo [4.2.0]Oct-2-en-3-yl]-1-methylpyrrolidinium hydrochloride of formula C19H24N6O5S2·2HCl·H2O, molecular weight 571.50, structural formula as follows:
cefepime hydrochloride has strong antibacterial activity and wide antibacterial spectrum, and has strong antibacterial activity on gram-positive bacteria and gram-negative bacteria including enterobacter, pseudomonas aeruginosa, haemophilus, neisseria, staphylococcus, streptococcus and the like. But the indications and new uses thereof are in need of further expansion.
Cefepime hydrochloride also produces a plurality of adverse reactions when being injected, and the most common is anaphylactic reaction. The anaphylaxis occurs rapidly, the treatment is difficult, and serious consequences can be caused once the treatment is not timely.
Although cefepime hydrochloride injection is an aseptic preparation, the adverse reaction is greatly reduced, but cefepime hydrochloride stability is poor due to residual or introduced impurities in the synthesis, purification and preparation of cefepime hydrochloride, cefepime hydrochloride forms a macromolecular polymer, and finally allergic reaction is caused. In addition, some impurities can cause pharmacological harm to human bodies and are not beneficial to human health.
In view of the above problems, the present inventors have conducted quality studies on cefepime hydrochloride, thereby providing a safe, effective and quality-controllable cefepime hydrochloride and a preparation thereof.
Disclosure of Invention
The inventor provides a cefepime hydrochloride compound with low impurity content by improving the raw material synthesis process through keen research; the process for preparing the cefepime hydrochloride compound can effectively control impurities in the product, is beneficial to improving the use safety of the product or a corresponding preparation, ensures the clinical treatment effect and improves the production efficiency, thereby completing the invention.
The invention aims to provide the following technical scheme:
in a first aspect, the present invention provides a preparation method of cefepime hydrochloride, which comprises the following steps:
step 1), adding ACLE & HCl and a reaction solvent I into a reaction container, dropwise adding an activating agent at 0-4 ℃, heating to react after dropwise adding is finished, and reacting the obtained reaction liquid with formic acid to generate a compound 1;
step 2), mixing the compound 1 with a reaction solvent II, dropwise adding trifluoroacetic acid (TFA) at 0-4 ℃, heating to react after dropwise adding, and then crystallizing to obtain a compound 2;
step 3), dropwise adding N-methylpyrrolidine into the compound 2 at 0-4 ℃, heating for reaction after dropwise adding is finished, and adding a crystallization solvent after the reaction is finished to obtain a compound 3;
step 4), removing 7-site amino protection from the compound 3 to obtain a compound 4;
and 5) mixing the compound 4 with a reaction solvent III, adding a catalyst and AE-active ester at the temperature of 20-30 ℃, adjusting the pH value with hydrochloric acid after the reaction is finished, and performing post-treatment to obtain a compound 5.
In a second aspect, the present invention provides cefepime hydrochloride prepared by the above preparation method, wherein cefepime hydrochloride (C) is an effective component18H16N8Na2O7S3·3.5H2O) is more than 98.00 percent.
The cefepime hydrochloride comprises an impurity A,
the impurity A is a nitrogen-containing impurity,
the mass content is not higher than 0.2%;
the impurity B is a nitrogen-containing impurity,
the impurity B is a nitrogen-containing impurity,
the mass content is not higher than 0.2%.
In a third aspect, the invention also provides a cefepime hydrochloride preparation taking cefepime hydrochloride as an effective component, wherein the preparation types comprise injections, granules, tablets, dripping pills and capsules, preferably injections,
the preparation can also comprise pharmaceutically acceptable pharmaceutic adjuvants without incompatibility, and the weight ratio of the cefepime hydrochloride to the pharmaceutic adjuvants is 10: (0.1-10).
In a fourth aspect, the invention also provides the cefepime hydrochloride and the cefepime hydrochloride preparation, and application of the cefepime hydrochloride and the cefepime hydrochloride preparation in preparation of a medicament for treating otitis media.
According to the cefepime hydrochloride, the preparation method and the application thereof provided by the invention, the cefepime hydrochloride has the following beneficial effects:
(1) according to the preparation method of cefepime hydrochloride provided by the invention, high content and low impurity of the raw material are effectively ensured, and the use safety and the clinical treatment effect of the corresponding preparation are favorably improved;
(2) compared with the prior method, the synthetic route of the invention does not use chlorofluorocarbon solvents (Freon TF and carbon tetrachloride) which are not beneficial to environmental protection;
in the synthetic route, each step of reaction can be carried out under mild conditions, and the reaction is not required under absolute dry conditions, so that the method has the advantage of large-scale production.
(3) The cefepime hydrochloride composition and the preparation thereof provided by the invention have the application of effectively preparing the medicament for treating otitis media.
Detailed Description
The present invention is further described below in terms of specific embodiments, and features and advantages of the present invention will become apparent as the description proceeds.
The invention aims to provide cefepime hydrochloride, and an effective component of cefepime hydrochloride (C) is required19H24N6O5S2·2HCl·H2O) is not less than 98.00%, preferably not less than 99.00%, more preferably not less than 99.50%, most preferably not less than 99.90% by mass.
Therefore, the inventor of the invention carries out long-term intensive research on a synthesis process of cefepime hydrochloride, so as to improve the effective content of cefepime hydrochloride in cefepime hydrochloride by obtaining cefepime hydrochloride with low impurity content, and further facilitate solving the problems of stability and medication safety of related preparations.
The inventor analyzes and summarizes a large amount of sample impurities in cefepime hydrochloride for injection produced by a plurality of manufacturers, and the problem that the stability of a finished product preparation in the storage process is further weakened due to the residue of raw material impurities and impurities generated in the production process in the finished product is possibly caused although the medicines for inspecting the impurities meet the quality requirements of Chinese pharmacopoeia, so that the method has important significance for fundamentally reducing the generation of the impurities. The inventors have found that impurities which are more commonly present in the product include:
the impurity A is a nitrogen-containing impurity,
in the reaction for producing cefepime hydrochloride, the strong acid is added and the contact time with water is too longAnd the four-membered ring of cefepime hydrochloride is unstable to generate impurities.
In order to reduce the generation and residue of impurities, the synthesis process of cefepime hydrochloride is improved, ACLE & HCl (7 β -amino-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester hydrochloride) is used as a starting material, 7-amino is protected by adopting formyl (-C ═ OH) which is easy to remove to obtain a compound 1, 4-ester is removed to obtain a compound 2, and the compound 2 is reacted with N-methylpyrrolidine (NMP, molecular formula: C ═ OH) in an organic solvent5H11N, molecular weight: 85.15) to generate a stable inner salt type compound 3, and then removing 7-amino protection to obtain a cefepime hydrochloride key intermediate compound 4.
Cheap and easily-obtained 2- (2-amino-4-thiazolyl) -2- (methoxyimino) thiobenzothiazole acetate (AE-active lipid for short) and a compound 4 are subjected to 7-bit acylation reaction to finally prepare cefepime 5 hydrochloride.
Specifically, the method comprises the following steps:
step 1), adding ACLE & HCl and a reaction solvent I into a reaction container, dropwise adding an activating agent at 0-4 ℃, heating to react after dropwise adding is finished, and reacting the obtained reaction liquid with formic acid to generate a compound 1;
step 2), mixing the compound 1 with a reaction solvent II, dropwise adding trifluoroacetic acid (TFA) at 0-4 ℃, heating to react after dropwise adding, and then crystallizing to obtain a compound 2;
step 3), dropwise adding N-methylpyrrolidine into the compound 2 at 0-4 ℃, heating for reaction after dropwise adding is finished, and adding a crystallization solvent after the reaction is finished to obtain a compound 3;
step 4), removing 7-site amino protection from the compound 3 to obtain a compound 4;
and 5) mixing the compound 4 with a reaction solvent III, adding a catalyst and AE-active ester at the temperature of 20-30 ℃, adjusting the pH value with hydrochloric acid after the reaction is finished, and performing post-treatment to obtain a compound 5.
In the step 1), ACLE & HCl and a reaction solvent I are added into a reaction vessel, an activating agent is dripped at the temperature of 0-4 ℃, after dripping is finished, heating reaction is carried out, and the obtained reaction liquid reacts with formic acid to generate a compound 1. The reaction formula is shown as the following formula (1):
according to the invention, ACLE & HCl is used as a reaction raw material, free ACLE hydrochloride is formed by ACLE & HCl through an activating agent, and then amino protection is carried out. Wherein the activating agent is any one or combination of triethylamine, pyridine and sodium bicarbonate, and triethylamine is preferred.
The activator is used for deprotonating ACLE & HCl, and theoretically, organic base and inorganic base can be selected, however, on one hand, the ACLE & HCl contains four-membered rings, strong acid or strong base is easy to form ring opening and affects the stability of raw materials, so that the strong base is not easy to use, and if the alkalinity is too weak, the deprotonation of the ACLE & HCl is incomplete; on the other hand, when an inorganic base is used, solvent water needs to be introduced into the system, and the presence of water in the system is unfavorable for the reaction in the subsequent amino protection process, so that the water introduced in the deprotonation process needs to be removed before the subsequent amino protection reaction, and compared with the use of an organic base, the use of the inorganic base makes the reaction procedure more complicated. The activator is selected from any one or combination of triethylamine, pyridine and sodium bicarbonate, and is preferably triethylamine.
In the present invention, the reaction solvent I is selected from one or a combination of Tetrahydrofuran (THF), methanol, or ethyl acetate (EtOAc), and is preferably tetrahydrofuran. The present inventors have surprisingly found that the use of tetrahydrofuran is more beneficial in increasing the yield of compound 1 than solvents such as ethyl acetate. The reason may be that the oxygen heterocyclic structure of tetrahydrofuran imparts an extremely strong polarity, which facilitates deprotonation of ACLE · HCl and maintains stability of the deprotonated ACLE hydrochloride, thereby facilitating the 7-amino protection reaction.
In the invention, the dosage of the ACLE HCl and the activating agent is calculated by the molar ratio of the ACLE HCl to the activating agent, and the molar ratio of the ACLE HCl to the activating agent is 1 (1-2). It was found that in this range of amounts, deprotonation of ACLE & HCl can be carried out efficiently, as evidenced by the yield of Compound 1. When the molar ratio is less than 1:0.5, the deprotonation efficiency of ACLE · HCl is low and incomplete; if the molar ratio of ACLE & HCl to the activating agent is higher than 1:2, the amount of the activating agent is higher, the deprotonation efficiency of ACLE & HCl is not obviously improved, and the raw material cost is increased.
In the invention, after the dropwise addition of the activating agent is finished, the temperature is raised to 20-35 ℃ for reaction, stirring is carried out in the reaction process, and the reaction time is 0.5-1 hour.
In the present invention, the reaction of the reaction solution after deprotonation of ACLE & HCl with formic acid comprises the following substeps:
substep 1-1), stirring and reacting formic acid and acetic anhydride for 0.5-2 h at 40-50 ℃;
substep 1-2), pouring the reaction liquid after deprotonation of ACLE & HCl into the system of substep 1-1), stirring and reacting for 0.5-2 h at 40-50 ℃, and precipitating crystals;
and substep 1-3), cooling the reaction system, stirring for 0.5-1.5 h at 0-4 ℃, filtering, and washing to obtain a compound 1.
The inventors found in their studies that the presence of water in the raw material during the amino group protection reaction reduces the reaction efficiency of the amino group protection, probably because the amino group protection reaction is a reaction to produce water, and the presence of water in the raw material inhibits the forward progress of the reaction. For this reason, substep 1-1) is designed, water carried in formic acid can be consumed and reaction raw material acetic acid is correspondingly generated by adding acetic anhydride, the concentration of the reaction raw material is improved, and the reaction raw material can also be used as a reaction solvent to participate in the subsequent substep 1-2); in substep 1-2), water molecules generated in the amino group protecting reaction can be consumed to further promote the reaction in the forward direction.
Preferably, the adding amount of the acetic anhydride is calculated according to the using amount ratio of the acetic anhydride to the ACLE & HCl, and the molar weight ratio of the acetic anhydride to the ACLE & HCl is (2-4): 1.
in the step 2), the compound 1 and a reaction solvent II are mixed, trifluoroacetic acid (TFA) is dropwise added at 0-4 ℃, the temperature is raised to 20-35 ℃ after the dropwise addition is finished, the reaction is carried out, and crystallization is carried out after the reaction is finished, so that the compound 2 is obtained. The reaction formula is shown as the following formula (2):
it was found that the amount of trifluoroacetic acid used in the synthesis of compound 2 had a significant effect on its yield. The molar ratio of the trifluoroacetic acid to the compound 1 is 5: 1-20: 1, preferably 8: 1-15: 1. When the ratio of the two is less than 5:1, the ester bond is insufficiently hydrolyzed; when the ratio of the two is more than 20:1, the stability of the beta-lactam four-membered ring is affected.
In a preferred embodiment of the invention, the reaction solvent II is a dichloromethane-anisole composite solvent, wherein the volume ratio of dichloromethane to anisole is (1-1.5): 1. wherein, the anisole belongs to a low-polarity solvent, which is beneficial to the participation of a trifluoroacetic acid solvent in the reaction.
In a preferred embodiment of the invention, the method is realized by pouring the reaction liquid after the temperature rise reaction into a crystallization solvent, wherein the crystallization solvent is a composite solvent of isopropyl ether and ethyl acetate, and the volume ratio of isopropyl ether to ethyl acetate is (0.5-2) to 1, preferably (0.9-1.1): 1. if the volume ratio of isopropyl ether to ethyl acetate is less than 0.5:1, the product yield is reduced; if the volume ratio of isopropyl ether to ethyl acetate is greater than 2: 1, the product impurities separated out are excessive. This is because ethyl acetate is likely to have more substances dissolved into ethyl acetate, and the yield is lowered by filtration.
In the step 3), dropwise adding N-methylpyrrolidine into the compound 2 at 0-4 ℃, heating for reaction after dropwise adding, and adding a crystallization solvent after reaction to obtain the compound 3. The reaction formula is shown as the following formula (3):
in a preferred embodiment, the reaction solvent for the reaction is one or a combination of tetrahydrofuran, methanol or N, N-dimethylformamide, N-dimethylacetamide, preferably tetrahydrofuran. The reason may be that the strongly polar structure of tetrahydrofuran, the product being a polar product, and the polar solvent, according to similar compatibility principles, helps to form more polar product, facilitating the formation and stabilization of polar compound 3.
In a preferred embodiment, the amount of N-methylpyrrolidine is such that the molar ratio of N-methylpyrrolidine to compound 2 is (2-3): 1.
In one embodiment, the crystallization solvent is selected from one or more of methanol, isopropanol, methyl ether, or ethyl acetate, preferably methanol.
In addition, the reaction liquid is poured into methanol, and the methanol is always in an excessive state, so that the crystal precipitation is facilitated.
In the invention, based on the reaction in the step 2), the conversion from 3-chloromethyl to 3-N-methylpyrrolidinium methyl can be directly realized in the step 3) by directly utilizing the activity of 3-halomethyl in the compound 2 without intermediate conversion, so that the reaction steps are simplified, and the use of expensive iodo reagent and TMSI (chlorotrimethylsilane) which is difficult to store is avoided.
In the step 3), due to the existence of the compound 3 (quaternary ammonium compound inner salt type structure), the compound has certain stability, and the tolerance to acid and alkali is increased, so that the existence of cephem isomer impurities is greatly reduced.
In the step 4) of the invention, the 7-amino protection of the compound 3 is removed to obtain a compound 4.
The deamination protection method can be a method commonly used in the field, and preferably adopts the following method:
adding concentrated hydrochloric acid into the mixture of the compound 3 and methanol, stirring for 3h, dripping the obtained mixed solution into a solution of ethyl acetate, filtering to obtain a white solid compound, and performing acetone-water treatment to obtain a white solid, namely a compound 4.
In the step 5), a compound 4(7 beta-amino-3- (1-methyl-1 pyrrolidinium) methyl-3-cephem-4-carboxylic acid double hydrochloride) and a reaction solvent III are mixed, a catalyst and AE-active lipid are added at 20-30 ℃, pH is adjusted by hydrochloric acid after the reaction is finished, and the compound 5 is obtained after post-treatment. The reaction formula is shown as the following formula (4):
in the present invention, the molar ratio of the compound 4 to the AE active lipid is 1 (1-2), preferably 1 (1.5-2). Within the dosage range, the selection of the catalyst and the reaction solvent is combined, so that the improvement of the reaction efficiency is facilitated.
In the invention, the reaction solvent III is a composite solvent of water-N, N-dimethylformamide, and the volume of the water-N, N-dimethylformamide is (0.4-0.6): 1, preferably 0.5: 1. When the moisture is excessive, hydrolysis of the product is easily caused, resulting in generation of impurities.
In the present invention, the catalyst in step 5) is an aliphatic amine, preferably one or more of pyridine, triethylamine, ethylenediamine, isopropylamine, diisopropylamine, n-butylamine, isobutylamine and 1, 4-butanediamine, and most preferably triethylamine.
In the prior art, inorganic base is generally used as a catalyst, the reaction temperature is required to be below 5 ℃, the requirements on production power and equipment are high, and the proportion of water in a reaction solvent needs to be increased. On the premise of not reducing the reaction conversion rate, the inventor conducts a great deal of research on the reaction conversion rate, and finds that the triethylamine is used as the catalyst, so that the reaction temperature can be increased, and the requirement on the temperature is relaxed. The reason may be that the organic base, particularly triethylamine, while promoting the reaction of compound 4 with the AE-active ester, is milder in reaction compared to the inorganic base, reducing the requirement for low temperatures.
In a preferred embodiment, the molar ratio of the catalyst to the compound 4 is (1-3): 1.
in the invention, hydrochloric acid is added to adjust the pH value to 1-3.
In step 5) of the present invention, the post-treatment comprises the steps of: pouring the reaction liquid of which the pH value is adjusted by hydrochloric acid into a crystallization solvent acetone, and separating out a product at room temperature due to the excessive state of the acetone, so that the reaction is rapid, and the reaction time and reaction equipment are saved; filtering, and washing by water-acetone (volume ratio is 1:1) to obtain a compound 5, wherein the compound 5 is cefepime hydrochloride.
In the invention, the volume ratio of the reaction solvent III to the crystallization solvent acetone is 1: (5-7).
The inventor analyzes the impurities of cefepime hydrochloride prepared by the method, and the impurity A
In the reaction for generating cefepime hydrochloride, the mass content of impurities generated by instability of a four-membered ring caused by the addition of strong acid and the overlong contact time with water is not higher than 0.2%, even not higher than 0.1%, even not higher than 0.05% and even not higher than 0.01%.
In the process of the present invention, the conversion rate of compound 4 directly affects the yield and purity of the final product, and when the reaction conditions are non-optimized conditions, compound 4 risks remaining in the product.
The impurity B is a nitrogen-containing impurity,
it is the residue of compound 4 in the product. Because the product is hydrochloride ions, the impurity B exists in an ion form under an acidic condition, and the mass content of the impurity B is not higher than 0.2%, or not higher than 0.1%, or not higher than 0.05%, or not higher than 0.01%.
In the invention, for the impurity A, organic amine is used as a catalyst in the step 5), so that the dosage of solvent water in a reaction system is reduced, the dosage of hydrochloric acid in subsequent pH value adjustment is further reduced, and the impact strength of the hydrochloric acid on the four-membered ring is relieved. The research finds that the impurity A can reduce the yield of the target product, and the method is favorable for solving the problem.
In the invention, for the impurity B, the conversion rate of the compound 4 is improved and the residue of the compound 4 in the system is reduced by using excessive amount of AE-active ester and specific selection of a catalyst. Researches find that the impurity B can cause insufficient reaction and cause raw material waste, and the method is favorable for solving the problem.
In the invention, the cefepime hydrochloride crystal obtained by the method is used for preparing a pharmaceutical preparation, which can be any pharmaceutically acceptable preparation type, including injections, granules, tablets, dripping pills, capsules and the like, or other medically usable carriers, preferably injections.
Preferably, the preparation can also comprise pharmaceutical excipients which are not incompatible in pharmacy, and the cefepime hydrochloride preparation comprises:
10 parts of cefepime hydrochloride;
0.1-10 parts of pharmaceutical excipients;
the pharmaceutical excipients are preferably one or more of osmotic pressure regulators, pH regulators and antioxidants. The osmotic pressure regulator is sodium chloride or glucose; the pH regulator is L-arginine; the antioxidant is one or more of vitamin C, sodium sulfite and sodium pyrosulfite.
In the invention, the cefepime hydrochloride preparation containing the pharmaceutic adjuvant is realized by the following steps: precisely weighing cefepime hydrochloride and pharmaceutic adjuvant according to a formula, wherein the particle size of cefepime hydrochloride D90 is 10-50 μm, and further is 20-40 μm; the particle size of the auxiliary material is 50-100 μm, preferably 50-80 μm; subpackaging according to a certain proportion or subpackaging after mixing; the two are preferably ground and mixed for split charging, so that the medicine and the auxiliary materials can be uniformly mixed, the particle size of the medicine can be further reduced, and the dissolving time in use can be shortened. The ball mill is preferably used for grinding and mixing, and due to the closed operation of the ball mill, sterile operation can be realized, the possibility of pollution is reduced, and the safety is improved.
According to the cefepime hydrochloride or the composition, the preparation method and the cefepime hydrochloride preparation provided by the invention, an application in preparing a medicament for treating otitis media is provided.
Examples
The invention is further illustrated by the following specific preferred examples. These examples are illustrative only and should not be construed as limiting the invention.
Example 1Synthesis of cefepime hydrochloride
Preparation of compound 1:
160g of ACLE HCl and 320mL of tetrahydrofuran are sequentially added into a reaction vessel, 55mL (0.39mol) of triethylamine is dropwise added under an ice bath, the ice bath is removed, and the mixture is stirred for 1h at room temperature. Filtering, washing with 150mL tetrahydrofuran for 3 times, and standing filtrate
Adding 44ml of formic acid and 110ml (1.17mol) of acetic anhydride into another reaction vessel, stirring and reacting for 0.5h at 40-50 ℃, pouring the filtrate for later use, separating out crystals, and continuing to react for 0.5h at 45 ℃. The temperature was reduced, stirred in ice bath for 1h, filtered and washed with ethanol to give 119g of compound 1 with a yield of 86%.
Preparation of compound 2:
110g of compound 1, 330mL of dichloromethane to 210mL of anisole (volume ratio is 3: 2) are sequentially added into a reaction vessel, 213mL of trifluoroacetic acid is dropwise added under ice bath, the mixture is stirred for 1 hour at room temperature, then the reaction solution is poured into a reaction bottle filled with 1200mL of isopropyl ether to 1200mL of ethyl acetate, and precipitate, namely 56g of compound 2, is collected by filtration, with the yield of 73%.
Preparation of compound 3:
50g of compound 2 and 200mL of tetrahydrofuran are added into a reaction vessel, 47mL of N-methylpyrrolidine is added dropwise in an ice bath, the mixture is stirred at room temperature for 0.5h after the dropwise addition, the reaction solution is poured into 90mL of methanol, and filtration is carried out to obtain 41g of compound 3 with the yield of 70%.
Preparation of compound 4:
32mL of concentrated hydrochloric acid was added to a mixture of 40g of compound 3 and 200mL of methanol, stirred for 3h, added dropwise to 200mL of ethyl acetate, filtered to obtain a white solid compound, which was treated with acetone-water (volume ratio 1:1) to obtain 37g of compound 4, yield 81%, and purity 98%.
Preparation of compound 5:
in a reaction vessel, 30g of compound 4, 300mL of water and 600mL of DMF were sequentially added, 22.8mL (0.16mol) of triethylamine was added at 20 ℃, the pH of the reaction solution was adjusted to 7, 29gAE of active lipid was added, the reaction was carried out at room temperature for 3 hours, the pH was adjusted to 1 with concentrated hydrochloric acid, the mixture was slowly poured into 6L of acetone, a white solid was obtained by filtration, and the mixture was washed three times with water-acetone (volume ratio 1:1) to obtain 34g of compound 5, yield 73%, and purity 99.88%.
Example 2Synthesis of cefepime hydrochloride
The same synthesis as in example 1, except that: in the synthesis of compound 1, ethyl acetate was used as reaction solvent I. The final preparation gave 74.7g of compound 1 in 54% yield, indicating that tetrahydrofuran as reaction solvent I favours an increase in conversion of the starting material over ethyl acetate.
Examples 3 to 4Synthesis of cefepime hydrochloride
Example 3 is the same as the synthesis process of example 1, except that: in the synthesis of compound 1, no acetic anhydride addition was involved in the amino protection with formic acid.
Example 4 is the same as the synthesis process of example 1, except that: in the synthesis of Compound 1, when the amino protection is carried out with formic acid, the amount of acetic anhydride added is 55ml (0.59 mol).
TABLE 1
| Examples | The amount of acetic anhydride used | Compound 1 | Yield of |
| Example 1 | 110ml | 119g | 86％ |
| Example 3 | Is free of | 50g | 36％ |
| Example 4 | 55ml | 86g | 62％ |
Table 1 shows that the addition of acetic anhydride is advantageous for the improvement of the conversion rate of the raw material, but if the amount of acetic anhydride is too small, the improvement of the conversion rate of the raw material is limited.
Example 5Synthesis of cefepime hydrochloride
The same synthesis as in example 1, except that: in the synthesis of compound 2, trifluoroacetic acid was used in an amount of 110ml (1.43mol) and the ratio to the molar amount of compound 1 was less than 5: 1. The final preparation gave 43g of Compound 2 in 56% yield, indicating that the use of too little trifluoroacetic acid was detrimental to the removal of the 4-ester group from Compound 1.
Example 6Synthesis of cefepime hydrochloride
The same synthesis as in example 1, except that: in the synthesis of compound 2, trifluoroacetic acid was used in an amount of 500ml (6.48mol) in a molar amount ratio of greater than 20:1 to compound 1. The final preparation gave 47g of Compound 2 in 61% yield, indicating that the use of excess trifluoroacetic acid resulted in the formation of by-products which in turn affected the yield of Compound 2.
Examples 7 to 9Synthesis of cefepime hydrochloride
The same synthesis as in example 1, except that: in the synthesis of the compound 2, the reaction solvent II and the crystallization solvent are selected differently.
TABLE 2
As can be seen from table 2, the combination of the reaction solvent II, a dichloromethane-anisole composite solvent, and a crystallization solvent, isopropyl ether-ethyl acetate composite solvent, facilitates the precipitation of the compound 2.
Examples 10 to 11Synthesis of cefepime hydrochloride
The same synthesis as in example 1, except that: in the synthesis of compound 3, the reaction solvent and the crystallization solvent are selected differently.
TABLE 3
| Examples | Reaction solvent | Crystallization solvent | Compound 3 | Yield of |
| Example 1 | Tetrahydrofuran (THF) | Methanol | 41g | 70％ |
| Example 10 | N, N-dimethylformamide | Methanol | 32g | 55％ |
| Example 11 | Tetrahydrofuran (THF) | Acetone (II) | 35g | 60％ |
As can be seen from table 3, the combination of the reaction solvent tetrahydrofuran and the crystallization solvent methanol is advantageous for increasing the conversion of compound 2.
Examples 12 to 14Synthesis of cefepime hydrochloride
The same synthesis as in example 1, except that: in the synthesis of the compound 5, the amount of AE active lipid added to the reaction system was varied.
TABLE 4
As is clear from Table 4, when the molar ratio of the compound 4 to the AE active ester is in the range of 1 (0.9 to 1.1), the yield of the compound 5 is high and the cost is low. When the molar ratio is higher than 1:2, the yield is not significantly improved.
Examples 15 to 17Synthesis of cefepime hydrochloride
The same synthesis as in example 1, except that: the amount of acetone used and/or the stirring rate varied during the synthesis of compound 5.
TABLE 5
As can be seen from table 5, when the volume ratio of the reaction solvent III to the crystallization solvent acetone is 1: (10-12), the stirring speed is 80-100 r/min, the yield of the prepared cefepime is high, and the bulk density and the angle of repose range are suitable for industrial preparation.
Example 18Synthesis of cefepime hydrochloride
The same synthesis as in example 1, except that: in the synthesis of compound 5, 30g of compound 4, 300mL of water and 600mL of DMF were sequentially added, and after adding a solid sodium hydroxide to the reaction mixture with cooling in an ice bath until the pH of the reaction mixture became 7, 29g of AE active lipid was added, and the reaction was carried out at room temperature for 3 hours. Namely, the catalyst is NaOH, and the water consumption in the system is correspondingly increased. 28g of compound 5 are finally obtained in 60% yield and 98.93% purity.
Example 19Cefepime hydrochloride-L-arginine powder injection
Pulverizing medicinal adjuvants L-arginine to D90 of 50-80 μm, weighing prepared pulverized cefepime hydrochloride 10kg and medicinal adjuvants 3.3kg, pulverizing and mixing with ball mill, and mixing with cefepime (C)19H24N6O5S2) And (4) counting 1g of the amount, sealing and packaging to obtain the cefepime hydrochloride preparation.
Examples of the experiments
Experimental example 1 quality measurement of cefepime hydrochloride crystals
1.1) Long term test
The content of cefepime hydrochloride and related substances obtained in examples 1, 13, 16 and 18 were measured according to the method of the pharmacopoeia cefepime hydrochloride of the 2015 edition under the conditions of 25 + -2 ℃ and 60 + -10% relative humidity, and the results are shown in the following table 6:
TABLE 6
Note: "not detected" means that the mass content is less than 0.01%.
1.2 accelerated test)
Samples of examples 1, 13, 16 and 18 were collected and stored for 6 months at 40. + -. 2 ℃ and 75. + -. 5% relative humidity according to a commercial package, and sampled at the end of 1, 3 and 6 months, respectively, and the results are shown in Table 7 below.
TABLE 7
The accelerated test results show that the detection of various indexes of the cefepime hydrochloride prepared by the invention has no obvious change, which indicates that the product has good stability.
Experimental example 2
Endotoxin/pyrogen studies were carried out on preparations of cefepime hydrochloride from examples 1, 13 and 16 prepared as described in example 19 and found to have endotoxin/pyrogen levels of less than 0.10EU/mg in each preparation.
Experimental example 3
Cefepime hydrochloride in examples 1, 13 and 16 cefepime hydrochloride formulations of cefepime-L-arginine hydrochloride were prepared as described in example 19, and the insoluble particles were studied according to the 2015 pharmacopoeia, with the results shown in table 8 below:
TABLE 8
It can be seen that cefepime hydrochloride preparations prepared from cefepime hydrochloride in examples 1, 13 and 16 have very good re-dissolving performance, and insoluble particles of more than 25 microns are few, so that clinical anaphylaxis is less caused.
Experimental example 4
Healthy female mice (4 weeks old, 18-20g in body weight) were inoculated with Escherichia coli 1 × 10 by tympanocentesis respectively6A mouse otitis media model was constructed to obtain model mice with middle ear infection.
60 middle ear infected mice were selected and divided into placebo and observation groups, each of which contained 30 mice. Taking the cefepime hydrochloride preparation of cefepime hydrochloride in example 1 prepared by the method in example 19, the preparation is respectively administrated to middle ear infection by tail vein injection of body weight of 110mg/kg (calculated by cefepime), and the administration frequency is 24 h; after 5 days of treatment, mice were sacrificed, dissected and middle ear infections were examined.
Treatment judgment criteria were given for fidgeting:
and (3) healing: the inflammatory symptoms completely disappeared;
improvement: the inflammatory symptoms have substantially disappeared;
the effect is shown: reduction of inflammatory symptoms;
and (4) invalidation: the inflammatory symptoms are essentially unchanged.
Wherein the treatment results of the middle ear infected mice are as follows:
observation group: the medicine can cure 20 patients, improve 4 patients, show 3 patients and have no effect on 3 patients.
Placebo group: 3 patients are cured, 4 patients are improved, 7 patients are obviously effective, and 16 patients are ineffective.
Therefore, the therapeutic effect of the observation group on the otitis media of the mice is obviously better than that of the placebo group.
Experimental example 5
260 healthy mice were collected and cefepime hydrochloride-L-arginine preparation prepared from cefepime hydrochloride in example 1 by the method in example 19 was administered by tail vein injection at a dose of 350mg/kg (calculated as cefepime), and the mice were observed for symptoms such as agitation, restlessness, nasal flaring, nasal grasping, shortness of breath, shrugging of hair, spasm of limbs, and jumping, and the mice were recorded for death.
The results are shown statistically as follows:
the mice showing the above symptoms had 3 mice in total, and none of the mice died. It is shown that cefepime hydrochloride prepared in example 1 has high safety and low allergenicity.
Experimental example 6
In healthy female SD rats (weight 180-7Model SD rats with middle ear infection were obtained.
100 middle-ear infected SD rats were selected and divided into placebo and observation groups, 50 of which were administered to each group. Taking the preparation A prepared by the method in example 19 of cefepime hydrochloride in example 1, the preparation A is respectively administrated to otitis media infection by tail vein injection of body weight of 110mg/kg (calculated by cefepime), and the administration frequency is 24 h; after 15 days of treatment, the rats were sacrificed, dissected and examined for middle ear infections.
Treatment judgment criteria were given for fidgeting:
and (3) healing: the inflammatory symptoms completely disappeared;
improvement: the inflammatory symptoms have substantially disappeared;
the effect is shown: reduction of inflammatory symptoms;
and (4) invalidation: the inflammatory symptoms are essentially unchanged.
Wherein the treatment result of the middle ear infected SD rat is
Observation group: 35 patients are cured, 6 patients are improved, 3 patients are obviously effective, and 6 patients are ineffective.
Placebo group: 4 patients are cured, 7 patients are improved, 9 patients are obviously effective, and 30 patients are ineffective.
Therefore, the therapeutic effect of the observation group on the otitis media of the rats is obviously better than that of the placebo group.
The invention has been described in detail with reference to specific embodiments and illustrative examples, but the description is not intended to be construed in a limiting sense. Those skilled in the art will appreciate that various equivalent substitutions, modifications or improvements may be made to the technical solution of the present invention and its embodiments without departing from the spirit and scope of the present invention, which fall within the scope of the present invention. The scope of the invention is defined by the appended claims.
Claims (10)
1. A preparation method of cefepime hydrochloride comprises the following steps:
step 1), adding ACLE & HCl and a reaction solvent I into a reaction container, dropwise adding an activating agent at 0-4 ℃, heating to react after dropwise adding is finished, and reacting the obtained reaction liquid with formic acid to generate a compound 1;
step 2), mixing the compound 1 with a reaction solvent II, dropwise adding trifluoroacetic acid (TFA) at 0-4 ℃, heating to react after dropwise adding, and then crystallizing to obtain a compound 2;
step 3), dropwise adding N-methylpyrrolidine into the compound 2 at 0-4 ℃, heating for reaction after dropwise adding is finished, and adding a crystallization solvent after the reaction is finished to obtain a compound 3;
step 4), removing 7-site amino protection from the compound 3 to obtain a compound 4;
and 5) mixing the compound 4 with a reaction solvent III, adding a catalyst and AE-active ester at the temperature of 20-30 ℃, adjusting the pH value with hydrochloric acid after the reaction is finished, and performing post-treatment to obtain a compound 5.
2. The preparation method according to claim 1, wherein in step 1), the activating agent is any one or a combination of triethylamine, pyridine and sodium bicarbonate, preferably triethylamine;
the molar ratio of ACLE & HCl to the activating agent is 1 (1-2).
3. The method according to claim 1, wherein the step 1) of reacting the reaction solution after deprotonation of ACLE-HCl with formic acid comprises the substeps of:
substep 1-1), stirring and reacting formic acid and acetic anhydride for 0.5-2 h at 40-50 ℃;
substep 1-2), pouring the reaction liquid after deprotonation of ACLE & HCl into the system of substep 1-1), stirring and reacting for 0.5-2 h at 40-50 ℃, and precipitating crystals;
and substep 1-3), cooling the reaction system, stirring for 0.5-1.5 h at 0-4 ℃, filtering, and washing to obtain a compound 1.
4. The preparation method according to claim 1, wherein in the step 2), the reaction solvent II is a dichloromethane-anisole composite solvent, wherein the volume ratio of dichloromethane to anisole is (1-1.5): 1;
the crystallization solvent is an isopropyl ether-ethyl acetate composite solvent, wherein the volume ratio of isopropyl ether to ethyl acetate is (0.9-1.1): 1.
5. the method according to claim 1, wherein in step 3), the amount of N-methylpyrrolidine is (2-3): 1, based on the molar ratio of N-methylpyrrolidine to Compound 2.
6. Cefepime hydrochloride characterized in that it is prepared by the process according to any one of claims 1 to 5, and has an effective component of cefepime hydrochloride (C)19H24N6O5S2·2HCl·H2O) is more than 98.00 percent.
7. Cefepime hydrochloride according to claim 6, comprising impurity A in cefepime hydrochloride,
the impurity A is a nitrogen-containing impurity,
the mass content is not higher than 0.2%.
8. Cefepime hydrochloride according to claim 6, further comprising impurity B,
the impurity B is a nitrogen-containing impurity,
the mass content is not higher than 0.2%.
9. A cefepime hydrochloride preparation, which comprises cefepime hydrochloride of any one of claims 6 to 8 or prepared by the preparation method of any one of claims 1 to 5 as an active ingredient, wherein the preparation types comprise injections, granules, tablets, dripping pills and capsules, preferably injections,
the preparation can also comprise pharmaceutically acceptable pharmaceutic adjuvants without incompatibility, and the weight ratio of the cefepime hydrochloride to the pharmaceutic adjuvants is 10: (0.1-10).
10. Use of cefepime hydrochloride according to any one of claims 6 to 8, cefepime hydrochloride prepared by the process according to any one of claims 1 to 5, a cefepime hydrochloride formulation according to claim 9, for the manufacture of a medicament for the treatment of otitis media.
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