CN111004255A - Preparation method of cefcapene lactone compound or hydrochloride thereof - Google Patents
Preparation method of cefcapene lactone compound or hydrochloride thereof Download PDFInfo
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- CN111004255A CN111004255A CN201911401553.7A CN201911401553A CN111004255A CN 111004255 A CN111004255 A CN 111004255A CN 201911401553 A CN201911401553 A CN 201911401553A CN 111004255 A CN111004255 A CN 111004255A
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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
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
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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
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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
- C07D501/12—Separation; Purification
Abstract
The invention relates to a preparation method of a cefcapene lactone compound or hydrochloride thereof, belonging to the technical field of synthesis of related impurities of medicaments. In order to solve the problems of few synthesis routes and low yield, the preparation method of the cefcapene lactone compound or the hydrochloride thereof is provided, and comprises the steps of carrying out condensation reaction on (Z) -2- (2-tert-butoxycarbonylaminothiazole-4-yl) -2-pentenoic acid and hydroxymethyl-7-aminocephalosporanic acid in an organic solvent in the presence of organic base, continuously adding the organic base to adjust the pH value to 9.0-9.5 after the condensation reaction is finished, and carrying out lactonization to obtain the compound shown in the formula IV: under the action of Lewis acid, carrying out deprotection reaction on the compound shown in the formula IV in a water-insoluble organic solvent to obtain the compound shown in the formula I: when synthesizing the cefcapene lactone compound hydrochloride, the method also comprises the step of reacting the compound shown in the formula I with hydrochloric acid to obtain the cefcapene lactone compound hydrochloride. Has the advantages of easy operation of the synthetic route and high yield and purity.
Description
Technical Field
The invention relates to a preparation method of a cefcapene lactone compound or hydrochloride thereof, belonging to the technical field of synthesis of related impurities of medicaments.
Background
Cefcapene Pivoxil Hydrochloride (Cefcapene Pivoxil Hydrochloride Hydrate) was developed by the Japanese Deseye corporation and first marketed under the trade name Flomox in 1997. Cefcapene pivoxil is the third generation orally administrable cephalosporins. Pharmacological research results show that the cephalocapecitabine has the characteristics of strong antibacterial activity and small dosage compared with the existing orally-administrable cephalosporin varieties, has good clinical effect and bacteriological effect on adults and children, has good safety, and is an orally-administrated cephalosporin with high curative effect.
The currently reported methods for synthesizing cefcapene pivoxil hydrochloride are more, but most processes are similar to the synthesis method reported in WO2008155615, and the synthesis route is as follows:
in the method, hydroxymethyl-7-aminocephalosporanic acid is used as an initial raw material, a cefcapene precursor sodium salt is obtained through a silanization reaction, a condensation reaction and an carbamylation reaction, then the cefcapene sodium salt reacts with iodomethyl pivalate to obtain tert-butoxycarbonyl cefcapene pivoxil, and finally the target product cefcapene pivoxil hydrochloride is synthesized through a deprotection reaction.
On the other hand, in the research and development process of new drugs or medicines, the quality of the drugs is an important standard for measuring the quality of the drugs, and the quality of the drugs firstly determines the curative effect and the toxic and side effect of the drugs, namely the effectiveness and the safety of the drugs. The content of the effective components of the medicine is an important mark for reflecting the purity of the medicine, and impurities in the medicine directly influence the curative effect of the medicine and can cause toxic and side effects. The presence of impurities not only affects the purity of the drug, but also brings non-therapeutic side effects and must be controlled. For safe and effective use of drugs, the quality standards of drugs have strict requirements on the purity of active ingredients of drugs and the limits of impurities, and generally, more than 0.1% of drug impurities should be identified and quantified by a selective method. For drug developers, the main work is not only to develop efficient synthesis process of raw drug materials, but also to study the types and sources of impurities in drugs and how to control the generation of process impurities. Generally, research personnel firstly directionally synthesize process impurities, secondly optimize the process to develop an efficient impurity synthesis route, and obtain high-quality impurity reference substances for the development of the quality research work of the bulk drugs.
For the impurity species and analysis of cefcapene pivoxil hydrochloride, there are 4 main impurities which are currently defined, including cefcapene pivoxil E-type isomer, cefcapene pivoxil delta 2 isomer, cefcapene pivoxil dimer and cefcapene acid, and for other impurities, only relevant impurities are adopted for identification, for example, for cefcapene lactone compound impurities mentioned in the synthesis of cefcapene pivoxil hydrochloride, the structural formula of the impurity compound is shown as the following formula:
the reports of the synthesis process of the impurities are quite few, and the impurities existing in the synthesis of cefcapene pivoxil hydrochloride are quite small in content and difficult to separate, so that the impurities with high quality are difficult to extract and serve as standard substances to serve as reference substances. Therefore, in order to better analyze the quality of cefcapene pivoxil hydrochloride and control impurities, the impurities in the cefcapene pivoxil hydrochloride can be better controlled in the synthesis process. It is necessary to provide efficient synthesis and high quality requirements for the impurities.
Disclosure of Invention
The invention provides a preparation method of cefcapene lactone compound or hydrochloride thereof aiming at the problems in the prior art, and aims to provide a method for efficiently synthesizing the cefcapene lactone compound or the hydrochloride thereof, wherein the synthesized product has high yield.
The invention aims to realize the following technical scheme, and the preparation method of the cefcapene lactone compound or the hydrochloride thereof is characterized by comprising the following steps of:
A. in the presence of a catalytic amount of organic base I, carrying out condensation reaction on a compound (Z) -2- (2-tert-butoxycarbonylaminothiazole-4-yl) -2-pentenoic acid shown in a formula II and hydroxymethyl-7-aminocephalosporanic acid shown in a formula III in an organic solvent, after the condensation reaction is finished, continuously adding organic base II to adjust the pH value of a system of reaction liquid to 9.0-9.5, and continuously stirring to fully lactonize an intermediate in the reaction liquid to obtain a lactonized intermediate compound shown in a formula IV:
B. under the action of Lewis acid, carrying out deprotection reaction on the intermediate compound shown in the formula IV in a water-insoluble organic solvent to remove BOC groups, and obtaining a corresponding product compound shown in the formula I:
when synthesizing cefcapene lactone compound hydrochloride, the following step C is also included after step B:
reacting the compound shown in the formula I with hydrochloric acid to obtain corresponding cefcapene lactone compound hydrochloride of the compound shown in the formula V:
the invention directly takes related raw materials (Z) -2- (2-tert-butyloxycarbonylaminothiazole-4-yl) -2-pentenoic acid and hydroxymethyl-7-aminocephalosporanic acid in the synthesis process of cefcapene pivoxil hydrochloride as raw materials for synthesizing the impurities, and takes organic base as the existence, and adopts catalytic amount of organic base to ensure the reaction during the early-stage condensation reaction, although the raw materials adopted in the invention are basically the same as the raw materials in the synthesis process of cefcapene pivoxil, the general conventional mode is subjected to acid adjustment treatment after the condensation is finished or directly used for synthesizing an intermediate in the next step, and a lactone compound does not occupy the dominant direction after the condensation, and only has a small amount of content as the impurity component; in the research and analysis process, the pH value of a system in a general reaction liquid is generally about 8.0-8.5 in the early-stage condensation reaction process, and the inventor finds that the pH value of the system is adjusted by directly and continuously adding organic base into the reaction liquid after the condensation reaction is finished and adjusting the pH value of the system to be 9.0-9.5 in the long-term research process, so that the formation of lactonization can be effectively promoted, a lactonization intermediate product is taken as a leading product, and the effect of high yield is realized; in addition, the step is critical to the control of the pH value, if the pH value of the system is too high, the alkalinity is too strong, but the ring opening and other damage phenomena of the cefuroxime mother lactam ring structure can occur, so that the yield of the product is obviously reduced, the generated byproducts are increased, the purity and quality requirements of the product are not ensured, and the quality is deteriorated; then, BOC removal protection reaction is carried out in the presence of Lewis acid, so that not only can BOC groups be effectively removed, but also the reaction product has the advantages of low impurity content and contribution to subsequent separation, and finally, the corresponding lactonization product with high yield can be obtained through subsequent treatment, and the lactonization product also has higher purity and quality requirements, so that the obtained lactonization product can be applied to a standard product in the cefcapene pivoxil synthesis process or product quality analysis as a reference product and the like, and better control and quality control of the cefcapene pivoxil hydrochloride are realized. Meanwhile, the raw materials used in the synthesis of cefcapene pivoxil hydrochloride are selected as the raw materials of the lactone, so that the lactone can be efficiently synthesized, the method is more beneficial to being applied to industrialization, the synthesis process of the method is simple and easy to operate, the obtained product can also have better yield and purity requirements, and the lactone product has the characteristics of high yield and high purity and can be suitable for large-scale production. When the cefcapene lactone compound hydrochloride needs to be synthesized, the corresponding hydrochloride can be obtained only by reacting the product with hydrochloric acid, and because the cefcapene lactone compound hydrochloride formed in the reaction process can be directly separated out, the problem of serious ring opening under a hydrochloric acid system can be basically avoided, and the stable separation out can be ensured.
In the above process for preparing cefcapene lactone compound or hydrochloride thereof, the organic base I and the organic base II are described for better presentation and are not only limited in the practical application, i.e. the organic base I and the organic base II may be the same or different, and it is of course preferable to use the same organic base before and after the process for preparing cefcapene lactone compound or hydrochloride thereof. Compared with inorganic base, the organic base I and the organic base II in the step A are more favorable for controlling the reaction to be carried out mildly, so that the reaction can be condensed and lactonized under milder conditions, and other unknown impurities are avoided. In order to make the reaction better proceed and fully form the lactonization product, preferably, the organic base I and the organic base II in the step A are respectively and independently one or more selected from triethylamine, diethylamine, pyridine, piperidine, diisopropylamine and pyrrole. That is, the organic base I and the organic base II are preferably selected from the organic bases mentioned above, and the organic bases are suitable in alkalinity, and the organic bases mentioned above can not only effectively promote the reaction, ensure the condensation reaction and promote the formation of the lactonization product, but also make the reaction proceed milder, facilitate the production operation, ensure the step has better conversion rate, and have the effect of high yield and high purity. Of course, for convenience of handling, it is preferable to use the same organic base for the first organic base and the second organic base, and to facilitate handling and control. As a further preferred example, the organic base is a mixture of triethylamine and diisopropylamine, and the ratio of the diisopropylamine to the triethylamine is 1: 0.2 to 0.3.
In the above method for preparing cefcapene lactone compound or hydrochloride thereof, the condensation reaction in step a is preferably carried out at a temperature of 0 to 10 ℃. The reaction can be carried out milder, and the quality of the intermediate of the reaction is further ensured. Furthermore, the reaction temperature of lactonization is controlled to be 15-25 ℃. Is more favorable for promoting the progress of lactonization reaction and further ensures the yield of the product.
In the above process for preparing cefcapene lactone compound or hydrochloride thereof, the organic solvent used in step A may be selected as requiredThe solvent is selected according to the needs of the art, for example, the solvent can be used in the corresponding step of the reaction of the two raw materials in the intermediate process of the synthesis of cefcapene pivoxil hydrochloride, and further, the organic solvent in the step can be selected from alcohols, esters, halogenated alkanes and the like. Alcohols such as C1-C4And esters such as ethyl acetate, ethyl methyl ester, etc., halogenated alkanes such as dichloromethane, chloroform, etc. And to better suit the overall process requirements for the synthesis of the cefcapene lactone compound. Preferably, the organic solvent in step a is one or more selected from ethanol, methanol, ethyl acetate and dichloromethane. Not only can effectively ensure the mild reaction, but also can make the subsequent treatment process easier to remove or separate the corresponding intermediate lactone compound. The amount of the organic solvent in the step can be determined according to the general dosage requirement, and of course, the amount of the organic solvent in the step is preferably 10 to 15 times of the amount of the hydroxymethyl-7-aminocephalosporanic acid compound in the formula III.
In the above process for producing a cefcapene lactone compound or a hydrochloride thereof, the lewis acid in step B is preferably selected from titanium tetrachloride and/or aluminum trichloride. The adoption of the Lewis acid can effectively promote the removal of BOC, can better avoid the generation of byproducts caused by the falling off of other groups, and is more favorable for improving the yield. As a further preferred, the lewis acid is titanium tetrachloride.
In the above method for preparing cefcapene lactone compound or hydrochloride thereof, the water-insoluble organic solvent in step B is preferably one or more selected from dichloromethane, chloroform and ethyl acetate. Not only can ensure the reaction, but also is more beneficial to the subsequent treatment, the production separation and the operation.
In the above method for preparing cefcapene lactone compound or hydrochloride thereof, after the reaction of removing BOC in the step B is finished, the method further comprises a post-treatment process, and the corresponding product is separated by post-treatment. In order to better improve the quality requirement of the separated product, the method preferably further comprises the following post-treatment after the deprotection reaction in the step B:
controlling the temperature of the reaction solution after the deprotection reaction to be between 15 and 25 ℃, adding a proper amount of water, stirring, standing for layering to remove a water phase, and collecting an organic phase;
and adding a proper amount of water into the collected organic phase, adding an inorganic alkali reagent to react and adjust the pH value of the system to 6.5-8.0, standing and layering to remove the water phase after the reaction is finished, and collecting the organic phase.
The impurities such as salts and the like which are easy to dissolve in water can be better removed through layered extraction, and acidic substances in the system, such as Lewis acid, and other impurities can be formed in the reaction by adding alkali to adjust the pH value of the system, so that the purity requirement of the product is further improved, the yield is ensured, the obtained product has better purity requirement, and the higher yield effect can be ensured. Further preferably, the pH of the system adjusted with the inorganic alkaline agent is preferably adjusted to 7.0 to 7.5. The acidic substance in the system can be better removed in the BOC group removal process, and other unnecessary impurities caused by overhigh alkalinity can be effectively avoided. The post-treatment process is carried out in combination with the subsequent synthesis of cefcapene lactone compound hydrochloride, which is more beneficial to control and operation.
In the above method for preparing cefcapene lactone compound or hydrochloride thereof, the deprotection reaction in step B is carried out at a temperature of 15 ℃ to 25 ℃. Can be finished under the condition of normal temperature basically, and is favorable for operation.
In the above method for preparing a cefcapene lactone compound or a hydrochloride thereof, the raw materials can be used in a suitable ratio according to the general molar equivalents in the reaction process, and preferably, the molar ratio of the compound (Z) -2- (2-tert-butoxycarbonylaminothiazole-4-yl) -2-pentenoic acid of formula ii to the compound hydroxymethyl-7-aminocephalosporanic acid of formula iii in step a is 1.0 to 1.5: 1.0, the molar ratio of the organic base I to the hydroxymethyl-7-aminocephalosporanic acid compound in the formula III is 1.0-1.5: 1.0; the molar ratio of the intermediate compound shown as the formula IV to the Lewis acid in the step B is 1.0: 1.5 to 3.0. The method can fully carry out the reaction and avoid the waste of raw materials, and reduce unnecessary post-treatment and impurity components brought by excessive raw materials, thereby being more beneficial to subsequent treatment and separation. The control of the dosage of the first organic base can better avoid side reactions such as ring opening of a cephalosporin mother lactam ring structure and the like in the condensation reaction process, and is also favorable for promoting the formation of subsequent lactonization products.
In the above method for preparing cefcapene lactone compound or hydrochloride thereof, the hydrochloric acid in step C can be directly subjected to salt-forming reaction by using concentrated hydrochloric acid, and certainly, the diluted hydrochloric acid can also be subjected to salt-forming reaction. Preferably, a small amount of alcohol solvent is added into the organic layer feed liquid collected in the step B, and then concentrated hydrochloric acid is dropwise added to carry out salt forming reaction. The system can be in a homogeneous phase state by adding a small amount of alcohol solvent, so that the reaction is more complete and the product is easier to separate out. The alcohol solvent is ethanol or methanol, and the amount of the alcohol solvent is generally 10-15% of the volume of the organic layer feed liquid.
The synthetic route of the preparation method of the cefcapene lactone compound or the hydrochloride thereof can be represented by the following reaction equation:
in summary, compared with the prior art, the invention has the following advantages:
the invention takes related raw materials (Z) -2- (2-tert-butyloxycarboryl aminothiazole-4-yl) -2-pentenoic acid and hydroxymethyl-7-aminocephalosporanic acid in the process of synthesizing cefcapene pivoxil hydrochloride as raw materials for synthesizing the impurities, and the reaction is carried out in the presence of organic alkali, and after the condensation is finished, the pH value of a system is directly adjusted to be within the range of 9.0-9.5 by using organic alkali, a lactonization intermediate can be efficiently formed, the requirements on better yield and purity are met, the product purity can reach more than 95.0 percent, the molar yield can reach more than 75.0 percent, the method can be used as a reference substance in analysis of high-purity cefcapene pivoxil hydrochloride to perform impurity analysis, ensures impurity control and purity quality analysis in the synthesis process of cefcapene pivoxil hydrochloride, and is more favorable for industrial application.
Detailed Description
The technical solution of the present invention is further specifically described below by way of specific examples, but the present invention is not limited to these examples.
Example 1
The compound of formula v, cefcapene lactone compound hydrochloride of this example, is represented by the following structural formula:
the synthesis of the cefcapene lactone compound hydrochloride is obtained by adopting the following method:
dissolving 30.2g (0.096mol, 1.2eq) of (Z) -2- (2-tert-butoxycarbonylaminothiazole-4-yl) -2-pentenoic acid and 18.4g (0.08mol, 1eq) of hydroxymethyl-7-aminocephalosporanic acid in 300mL of ethyl acetate at normal temperature, slowly cooling to 5-10 ℃, controlling the temperature, beginning to dropwise add 10.5g (0.104mol,1.3eq) of triethylamine, controlling the temperature to 5-10 ℃ after dropwise adding, and stirring for condensation reaction for 3 hours; after the condensation reaction is finished, triethylamine is dripped into the reaction liquid, the pH value of a system of the reaction liquid is adjusted to be 9.0-9.5, after the pH value is basically stable, the temperature is controlled to be about 15 ℃, stirring is carried out for full lactonization reaction for 2 hours, after the lactonization is finished, reduced pressure concentration is carried out until a certain volume is removed, then, the temperature is slowly reduced to-10 to-5 ℃, stirring is carried out for crystallization for 2 hours, after the crystallization is finished, filtration is carried out, a filter cake is washed by a small amount of ethyl acetate, an obtained wet product is placed in a vacuum oven, drying treatment is carried out at the temperature of about 35 ℃, and after drying, 36.3g of the intermediate compound lactone compound of the formula IV is obtained, and the molar yield is 92%.
Adding 225g of ethyl acetate into another clean reaction bottle at normal temperature, adding 11.3g (0.023mol, 1eq) of the intermediate IV compound lactone compound, stirring and dissolving fully, controlling the temperature to be 15-20 ℃, slowly adding 8.7g (0.046mol, 2eq) of titanium tetrachloride, controlling the temperature to be 15-20 ℃ after adding, stirring and reacting for 20 minutes, controlling the temperature to be 15-20 ℃ after the reaction is finished, obtaining a corresponding reaction solution containing the cefcapene lactone compound of the compound I, continuously controlling the temperature to be 15-20 ℃, adding 120g of water into the reaction solution, controlling the temperature to be 15-20 ℃, stirring and washing for 10 minutes, standing and separating, removing a water layer after full layering, collecting an organic layer, adding 100g of water into the organic layer, controlling the temperature to be 15-20 ℃, adjusting the pH value of the system to be 7.2 by using a proper amount of 6% sodium hydroxide aqueous solution, stirring and reacting for 20 minutes, standing and fully layering, separating to remove the water layer, and collecting the organic layer; and controlling the temperature to be 15-20 ℃, slowly dropwise adding 63g of concentrated hydrochloric acid into the collected organic layer feed liquid, adjusting the pH value to 3.0, separating out a product in the process of dropwise adding the concentrated hydrochloric acid, slowly cooling to 5-10 ℃ after the addition is finished, carrying out heat preservation and crystallization for 1.5 hours, ensuring sufficient crystallization by cooling, filtering after the crystallization is finished, leaching a filter cake with 80g of water, drying the obtained wet product at 35-40 ℃ in vacuum, and drying to obtain 8.4g of cefcapene lactone compound hydrochloride of the compound V, wherein the molar yield is about 85.2%, and the purity of the product is 95.80% by HPLC (high performance liquid chromatography).
The structure of the obtained cefcapene lactone compound hydrochloride of the compound shown in the formula V is confirmed and analyzed, and the analysis result is as follows:
mass Spectrometry (MS) analysis of the hydrochloride salt of cefcapene lactone compound is as follows:
the molecular formula is as follows: c16H16N4O4S2·HCl
Absolute molecular weight: 428.95
According to the mass spectrum of the sample, under the positive ion mode, a stronger ion peak at M/z 393.1 corresponds to [ M + H ] of the sample]+A signal; in negative ion mode, the stronger ion peak at M/z 427.0 corresponds to [ M + Cl ] of the sample]-A signal; the above test results are consistent with the molecular weight of cefcapene lactone compound hydrochloride.
Nuclear magnetic spectrum analysis of cefcapene lactone compound hydrochloride of formula V13C-NMR and1analysis of H-NMR spectrum data, to more conveniently illustrate the position of each atom in the structure, cefcapene lactone in the structural formula of the hydrochloride of the cefcapene lactone compound is marked, and the structural formula is shown as follows:
in particular13C-NMR and1the analysis of the H-NMR spectrum data is shown in the following tables 1 and 2:
wherein, Table 1 shows the nuclear magnetic spectrum of the hydrochloride of the cefcapene lactone compound of the formula V13C-NMR analysis; TABLE 2 nuclear magnetic spectrum of cefcapene lactone compound hydrochloride of formula V1H-NMR analysis;
table 1:
the results of the data presented in table 1 above show that,13the C-NMR spectrum data showed that the sample contained 15 sets of 16 carbon signals in total, each of which was a signal for 3 carbonyl carbons (. delta.)C170.200/169.579s；δC166.505/166.450s；δC166.095/165.508s), 1 imine carbon signal (. delta.))C163.097/163.007s), 4 heterocyclic quaternary carbon signals (. delta.))C148.096/135.416s；δC142.390/142.012s×2；δC127.048/124.252s), 2 double bond methine signals (. delta.))C122.768/122.737s；δC107.771/103.771s), 2 other methines (. delta.) as well as their use in the preparation of medicamentsC60.157/59.825s；δC57.457/57.371s), 1 oxymethylene group (. delta.) (C71.471/71.449s), 2 long-chain methylene groups (. delta.))C22.918/22.876s；δC22.692/22.490s) and 1 methyl signal (. delta.) (delta.)C13.480/13.068 s). The analysis result is consistent with the structure of the cefcapene lactone compound.
Table 2:
the results of the data presented in table 2 above show that,19 groups of proton signals appearing in an H-NMR spectrum are obtained according to the integral area ratio of 1:1:1:1:1:2:3:3:3, so that the proton signals delta containing at least 14 hydrogen atoms (part of active hydrogen is not shown) and including 1 bimodal secondary amine group in the sample are obtainedH9.575-9.559/9.103-9.087(d, J ═ 8.0Hz,2H), 1 trimodal double bond signal δH6.917-6.888/6.414-6.384(t, J ═ 7.5Hz,1H), 3 heterocyclic last methyl signal (δH6.786/6.490,s,1H；δH5.927-5.901/5.878-5.852,dd,J＝8.0,5.0Hz,1H；δH5.201-5.191/5.149-5.139, d, J ═ 5.0Hz,1H), 1 oxygen-containing monomodal methylene proton signal δH5.056(s,2H), 2 multiplet methylene signals δH3.872-3.771(m,2H) and δH2.279-2.171(m,2H) and 1 multiple peak methyl signal deltaH1.045-1.001(m, 3H). The analysis result is consistent with the structure of the cefcapene lactone compound.
The following Table 3 shows the infrared absorption spectrum (IR) data and the resolution of the hydrochloride salt of the corresponding cefcapene lactone compound of the formula V:
table 3:
the IR spectrum analysis data in Table 3 above shows that 3414cm-1、3376cm-1Is an N-H asymmetric and symmetric stretching vibration absorption peak of primary amine, 3287cm-1Is the N-H stretching vibration absorption peak of secondary amine, 1097cm-1、1025cm-1Absorption peak of (1) 1805cm-1、1785cm-1、1753cm-1C ═ O stretching vibration for carbonyl group, 1444cm-1、1419cm-1、1353cm-1、1312cm-1、1245cm-1The C-N stretching vibration absorption peak (overlapping with alkane) of the amino group indicates that the compound has a structure such as amide or ester.
1586cm-1、1572cm-1、1525cm-1The strong absorption peak is the stretching vibration of the double bond C ═ C, and it is found that the molecule contains the double bond.
3099cm-1、3037cm-1、2974cm-1Is C-H stretching vibration absorption peak of alkane, 1444cm-1、1419cm-1、1353cm-1、1312cm-1、1245cm-1Is C-H bending vibration absorption peak of alkane, 984cm-1、967cm-1The alkane exists in the molecule as the out-of-plane bending vibration absorption peak of the alkane C-H.
As can be seen, the infrared absorption spectrum shows that the sample molecule contains amide, ester, double bond, alkane and other characteristic functional groups, and the structure of the compound is consistent with that of the compound cefcapene lactone hydrochloride of the formula V.
By the above-mentioned MS,13C-NMR、1Analysis of H-NMR and IR spectrum data can confirm that the obtained product is the corresponding V compound, namely cefcapene lactone compound hydrochloride.
Example 2
Dissolving 37.7g (0.12mol,1.5eq) of (Z) -2- (2-tert-butoxycarbonylaminothiazole-4-yl) -2-pentenoic acid and 18.4g (0.08mol, 1eq) of hydroxymethyl-7-aminocephalosporanic acid in 400mL of dichloromethane at normal temperature, slowly cooling to 5-10 ℃, controlling the temperature, beginning to dropwise add 10.5g (0.104mol,1.3eq) of triethylamine, controlling the temperature to 0-5 ℃ after dropwise adding, and stirring for condensation reaction for 4 hours; after the condensation reaction is finished, dropwise adding into the reaction liquid, dropwise adding triethylamine into the reaction liquid, adjusting the pH value of a system of the reaction liquid to 9.0-9.5, after the pH value is basically stable, controlling the temperature to be about 15 ℃, stirring for full lactonization reaction for 3.0 hours, after the lactonization is finished, carrying out reduced pressure concentration to a certain volume to remove part of the solvent, slowly cooling to-10 to-5 ℃, stirring for crystallization for 2 hours, after the crystallization is finished, filtering, washing a filter cake with a small amount of ice dichloromethane, placing an obtained wet product into a vacuum oven, controlling the oven temperature to be about 35 ℃, carrying out drying treatment, and after drying, obtaining 36.7g of the intermediate compound lactone compound of the IV compound, wherein the molar yield is 93%.
Adding 250g of dichloromethane into a clean reaction bottle at normal temperature, adding 11.3g (0.023mol, 1eq) of the intermediate IV compound lactone compound, stirring and dissolving the dichloromethane fully, controlling the temperature to be 20-25 ℃, slowly adding 6.6g (0.035mol, 1.5eq) of titanium tetrachloride, controlling the temperature to be 20-25 ℃ after the addition is finished, stirring and reacting the mixture for 25 minutes, controlling the temperature to be 20-25 ℃ after the reaction is finished, obtaining a corresponding reaction solution containing the cefcapene lactone compound of the compound I, continuously controlling the temperature to be 20-25 ℃, adding 130g of water into the reaction solution, controlling the temperature to be 20-25 ℃, stirring and washing the reaction solution for 10 minutes, standing and separating the solution, removing a water layer after the solution is separated fully, collecting an organic layer, adding 100g of water into the organic layer, controlling the temperature to be 20-25 ℃, adjusting the pH value of the system to be 7.5 by using a proper amount of 6% sodium hydroxide aqueous solution, stirring and reacting for 20 minutes, standing and fully separating the layer, separating to remove the water layer, and collecting the organic layer; and controlling the temperature to be 20-25 ℃, slowly dropwise adding 65g of concentrated hydrochloric acid into the collected organic layer feed liquid, adjusting the pH value to 2.5, then slowly cooling to 5-10 ℃, preserving heat, then crystallizing for 1.5 hours, filtering after crystallization is finished, leaching a filter cake with 80g of water, drying an obtained wet product at 35-40 ℃ in vacuum, and drying to obtain 8.5g of cefcapene lactone compound hydrochloride of the compound V, wherein the molar yield is about 86.1%, and the purity of the product is 96.3% by HPLC (high performance liquid chromatography).
The structure of the obtained cefcapene lactone compound hydrochloride is confirmed and analyzed, and the analysis result shows that the structure of the obtained cefcapene lactone compound hydrochloride is consistent with that of the cefcapene lactone compound hydrochloride in the example 1, which shows that the corresponding compound of the formula V, namely the cefcapene lactone compound hydrochloride, is obtained.
Example 3
Dissolving 27.7g (0.088mol,1.1eq) of (Z) -2- (2-tert-butoxycarbonylaminothiazole-4-yl) -2-pentenoic acid and 18.4g (0.08mol, 1eq) of hydroxymethyl-7-aminocephalosporanic acid in 400mL of ethyl acetate at normal temperature, slowly cooling to 5-8 ℃, controlling the temperature, beginning to dropwise add 12.1g (0.12mol,1.5eq) of triethylamine, controlling the temperature to 0-5 ℃ after dropwise adding, and stirring for condensation reaction for 3.5 hours; after the condensation reaction is finished, triethylamine is dripped into the reaction liquid, the pH value of a system of the reaction liquid is adjusted to be 9.0-9.5, after the pH value is basically stable, the temperature is controlled to be about 20 ℃, stirring is carried out for full lactonization reaction for 3 hours, after the lactonization is finished, reduced pressure concentration is carried out until a certain volume is removed, then, the temperature is slowly reduced to-8 to-5 ℃, stirring is carried out for crystallization for 2.5 hours, after the crystallization is finished, filtration is carried out, a filter cake is washed by a small amount of ethyl glacial acetate, an obtained wet product is placed in a vacuum oven, the temperature of the oven is controlled to be about 35 ℃, drying is carried out, 36.8g of the intermediate compound lactonization is obtained, and the molar yield is 93.5%.
Adding 230g of ethyl acetate into a clean reaction bottle at normal temperature, adding 11.3g (0.023mol, 1eq) of the intermediate IV compound lactone obtained, stirring and dissolving fully, controlling the temperature to be 18-22 ℃, slowly adding 10.9g (0.058mol,2.5eq) of titanium tetrachloride, controlling the temperature to be 18-22 ℃ after adding, stirring and reacting for 30 minutes, controlling the temperature to be 18-22 ℃ after the reaction is finished, obtaining a corresponding reaction liquid containing the cefcapene lactone compound of the compound I, continuously controlling the temperature to be 18-22 ℃, adding 120g of water into the reaction liquid, controlling the temperature to be 18-22 ℃, stirring and washing for 10 minutes, standing and separating, after full layering, separating and discarding the water layer, collecting the organic layer, adding 100g of water into the organic layer, controlling the temperature to be 18-22 ℃, regulating the pH value of the system to be 7.0-8.0 by using a proper amount of 8% sodium hydroxide aqueous solution, stirring and reacting for 20 minutes, standing and fully layering, removing a water layer from the liquid, collecting an organic phase, controlling the temperature to be 18-22 ℃, adding 50mL of a small amount of ethanol into the collected organic layer feed liquid, slowly dropwise adding a proper amount of concentrated hydrochloric acid into the collected organic layer feed liquid, adjusting the pH value to be 2.0, slowly cooling to 0-5 ℃, preserving heat, then crystallizing for 1.5 hours, filtering after crystallization is finished, leaching a filter cake with 80g of water, drying the obtained wet product at 35-40 ℃ in vacuum, and drying to obtain 8.8g of cefcapene lactone compound hydrochloride of the compound V, wherein the molar yield is about 89.3%, and the purity of the product is 97.1% by HPLC (high performance liquid chromatography).
The structure of the obtained cefcapene lactone compound hydrochloride is confirmed and analyzed, and the analysis result shows that the structure of the obtained cefcapene lactone compound hydrochloride is consistent with that of the cefcapene lactone compound hydrochloride in the example 1, which shows that the obtained product is the corresponding cefcapene lactone compound hydrochloride of the compound shown in the formula V.
Example 4
Dissolving 32.7g (0.104mol,1.3eq) of (Z) -2- (2-tert-butoxycarbonylaminothiazole-4-yl) -2-pentenoic acid and 18.4g (0.08mol, 1eq) of hydroxymethyl-7-aminocephalosporanic acid in 300mL of ethyl acetate at normal temperature, slowly cooling to 5-10 ℃, controlling the temperature, beginning to dropwise add 8.2g (0.104mol,1.3eq) of pyridine, controlling the temperature to 5-10 ℃ after dropwise adding, and stirring for condensation reaction for 3 hours; after the condensation reaction is finished, adding pyridine into the reaction liquid dropwise, adjusting the pH value of the system of the reaction liquid to 9.0-9.2, after the pH value is basically stable, controlling the temperature to be about 15 ℃, stirring for full lactonization reaction for 3 hours, after the lactonization is finished, carrying out reduced pressure concentration to a certain volume to remove part of the solvent, then slowly cooling to-10 to-5 ℃, stirring for crystallization for 2 hours, after the crystallization is finished, filtering, washing a filter cake with a small amount of ethyl acetate, placing the obtained wet product in a vacuum oven, controlling the temperature of the oven to be about 35 ℃, carrying out drying treatment, and obtaining 36.5g of the intermediate compound lactonization product of the formula IV, wherein the molar yield is 92.5%.
Adding 225g of ethyl acetate into a clean reaction bottle at normal temperature, adding 11.3g (0.023mol, 1eq) of the obtained intermediate lactone compound, stirring and dissolving fully, controlling the temperature to be 15-18 ℃, slowly adding 6.1g (0.046mol, 2eq) of aluminum trichloride, controlling the temperature to be 15-18 ℃ after the addition is finished, stirring and reacting for 30 minutes, obtaining corresponding reaction liquid containing the cefcapene lactone compound of the compound shown in the formula I after the reaction is finished, and directly removing the solvent to obtain a corresponding product. Controlling the temperature to be 15-18 ℃ continuously, adding 150g of water into a reaction solution, controlling the temperature to be 15-18 ℃, stirring and washing for 15min, standing and separating, removing a water layer after full layering, collecting an organic layer, adding 100g of water into the organic layer, controlling the temperature to be 15-18 ℃, adjusting the pH value of a system to be 7.0 by using a proper amount of 6% sodium hydroxide aqueous solution, stirring and reacting for 30 min, standing and fully layering, removing the water layer after separating, collecting the organic layer, controlling the temperature to be 15-18 ℃, slowly dripping a proper amount of concentrated hydrochloric acid into the collected organic layer feed liquid, adjusting the pH value to be about 2.5, slowly cooling to 5-10 ℃, carrying out thermal insulation and crystallization for 1.5 h, filtering after crystallization is finished, leaching a filter cake by using 80g of water, drying an obtained wet product at 35-40 ℃ under vacuum, drying, obtaining 8.5g of the cefcapene lactone compound V of the formula, the molar yield was about 86.1% and the product purity was 95.9% by HPLC.
The structure of the obtained cefcapene lactone compound hydrochloride is confirmed and analyzed, and the analysis result shows that the structure of the obtained cefcapene lactone compound hydrochloride is consistent with that of the cefcapene lactone compound hydrochloride in the example 1, so that the obtained corresponding product is the compound of the formula V, namely the cefcapene lactone compound hydrochloride.
Example 5
At normal temperature, dissolving 27.7g (0.088mol,1.1eq) of (Z) -2- (2-tert-butoxycarbonylaminothiazole-4-yl) -2-pentenoic acid and 18.4g (0.08mol, 1eq) of hydroxymethyl-7-aminocephalosporanic acid in a mixed solvent of 300mL of ethyl acetate and 50mL of ethanol, slowly cooling to 5-10 ℃, controlling the temperature, beginning to dropwise add 8.9g (0.088mol,1.1eq) of diisopropylamine, controlling the temperature to 5-10 ℃ after dropwise adding, and stirring for condensation reaction for 3 hours; after the condensation reaction is finished, adding diisopropylamine dropwise into the reaction liquid, adjusting the pH value of the system of the reaction liquid to 9.2-9.5, after the pH value is basically stable, controlling the temperature to be about 15 ℃, stirring for full lactonization reaction for 2 hours, after the lactonization is finished, carrying out reduced pressure concentration to a certain volume to remove part of the solvent, then slowly cooling to-10-5 ℃, stirring for crystallization for 2 hours, after the crystallization is finished, filtering, washing a filter cake with a small amount of ethyl acetate, placing the obtained wet product in a vacuum oven, controlling the temperature of the oven to be about 35 ℃, carrying out drying treatment, and obtaining 36.1g of the intermediate IV compound lactonization product with the molar yield of 91.7%.
And adding 225g of chloroform into a clean reaction bottle at normal temperature, adding 11.3g (0.023mol, 1eq) of the obtained intermediate lactone compound, stirring, slowly adding 9.15g (0.069mol, 3eq) of aluminum trichloride at the temperature of 15-18 ℃, controlling the temperature to be 18-20 ℃ after the addition is finished, stirring for reacting for 30 minutes, obtaining a corresponding reaction solution containing the cefcapene lactone compound of the compound shown in the formula I after the reaction is finished, and directly removing the solvent to obtain a corresponding product. If the temperature is controlled to be 18-20 ℃ continuously for synthesizing cefcapene lactone compound hydrochloride, adding 150g of water into the reaction liquid, controlling the temperature to be 15-18 ℃, stirring and washing for 15min, standing and separating the liquid, removing a water layer after full layering, collecting an organic layer, adding 100g of water into the organic layer, controlling the temperature to be 18-20 ℃, adjusting the pH value of the system to be 7.2 by using a proper amount of 6% sodium hydroxide aqueous solution, stirring and reacting for 30 min, standing and fully layering, separating the liquid and removing the water layer, collecting the organic layer, controlling the temperature to be 18-20 ℃, slowly dripping a proper amount of concentrated hydrochloric acid into the collected organic layer liquid, adjusting the pH value to be about 2.3, then slowly cooling to 5-10 ℃, carrying out thermal insulation crystallization for 1.5 h, filtering after crystallization is finished, leaching a filter cake by using 80g of water, drying the obtained wet product at 35-40 ℃ in vacuum, drying to obtain 8.4g of the cefcapene lactone compound hydrochloride of the formula V, the molar yield was about 85.2% and the product purity was 95.5% by HPLC.
The structure of the obtained cefcapene lactone compound hydrochloride is confirmed and analyzed, and the analysis result shows that the structure of the obtained cefcapene lactone compound hydrochloride is consistent with that of the cefcapene lactone compound hydrochloride in the example 1, which shows that the obtained corresponding product is the compound of the formula V, namely the cefcapene lactone compound hydrochloride.
Example 6
Dissolving 37.7g (0.12mol,1.5eq) of (Z) -2- (2-tert-butoxycarbonylaminothiazole-4-yl) -2-pentenoic acid and 18.4g (0.08mol, 1eq) of hydroxymethyl-7-aminocephalosporanic acid in 200mL of ethyl acetate at normal temperature, slowly cooling to 5-10 ℃, controlling the temperature, beginning to dropwise add 8.9g (0.104mol,1.3eq) of piperidine, controlling the temperature to 0-5 ℃ after dropwise adding, and stirring for condensation reaction for 3.5 hours; after the condensation reaction is finished, adding piperidine dropwise into the reaction liquid, adjusting the pH value of the system of the reaction liquid to 9.0-9.2, after the pH value is basically stable, controlling the temperature to be about 15 ℃, stirring for full lactonization reaction for 3 hours, after the lactonization is finished, carrying out reduced pressure concentration to a certain volume to remove part of the solvent, then slowly cooling to-10 to-5 ℃, stirring for crystallization for 2 hours, after the crystallization is finished, filtering, washing a filter cake with a small amount of ethyl glacial acetate, placing the obtained wet product in a vacuum oven, controlling the temperature of the oven to be about 35 ℃, carrying out drying treatment, and obtaining 36.7g of the intermediate IV compound lactonization product with the molar yield of 93.2%.
Adding 250g of dichloromethane into a clean reaction bottle at normal temperature, adding 11.3g (0.023mol, 1eq) of the obtained intermediate lactone compound, stirring and dissolving fully, controlling the temperature to be 20-23 ℃, slowly adding 6.6g (0.035mol, 1.5eq) of titanium tetrachloride, controlling the temperature to be 20-23 ℃ after adding, stirring and reacting for 25 minutes, controlling the temperature to be 20-23 ℃ after the reaction is finished, obtaining a corresponding reaction solution containing the cefcapene lactone compound of the compound I, continuously controlling the temperature to be 20-23 ℃, adding 150g of water into the reaction solution, controlling the temperature to be 20-23 ℃, stirring and washing for 10 minutes, standing and separating, removing a water layer after separating and fully layering, collecting an organic layer, adding 100g of water into the organic layer, controlling the temperature to be 20-25 ℃, adjusting the pH value of the system to be 6.5 by using a proper amount of 6% sodium hydroxide aqueous solution, stirring and reacting for 20 minutes, standing and removing the water layer after fully layering, collecting an organic layer, controlling the temperature to be 20-25 ℃, slowly dripping a proper amount of concentrated hydrochloric acid into the collected organic layer feed liquid, adjusting the pH value to be 2.2, then slowly cooling to 5-10 ℃, carrying out heat preservation and crystallization for 1.5 hours, filtering after crystallization is finished, leaching a filter cake with 80g of water, drying an obtained wet product at 35-40 ℃ in vacuum, drying to obtain 8.4g of cefcapene pivoxil compound hydrochloride of the compound V, wherein the molar yield is about 85.2%, and the purity of a product is 96.1% by HPLC (high performance liquid chromatography).
The structure of the obtained cefcapene lactone compound hydrochloride is confirmed and analyzed, and the analysis result shows that the structure of the obtained cefcapene lactone compound hydrochloride is consistent with that of the cefcapene lactone compound hydrochloride in the example 1, which shows that the corresponding compound of the formula V, namely the cefcapene lactone compound hydrochloride, is obtained.
Example 7
Dissolving 37.7g (0.12mol,1.5eq) of (Z) -2- (2-tert-butoxycarbonylaminothiazole-4-yl) -2-pentenoic acid and 18.4g (0.08mol, 1eq) of hydroxymethyl-7-aminocephalosporanic acid in 400mL of ethyl acetate at normal temperature, slowly cooling to 5-10 ℃, controlling the temperature, beginning to dropwise add a mixed organic base of 8.1g (0.08mol, 1.0eq) of diisopropylamine and 1.6g (0.016mol,0.2eq) of triethylamine, controlling the temperature to 0-5 ℃ after dropwise adding, and stirring for condensation reaction for 3.5 hours; after the condensation reaction is finished, adding diisopropylamine dropwise into the reaction liquid, adjusting the pH value of the system of the reaction liquid to 9.0-9.2, after the pH value is basically stable, controlling the temperature to be about 15 ℃, stirring for full lactonization reaction for 3 hours, after the lactonization is finished, carrying out reduced pressure concentration to a certain volume to remove part of the solvent, then slowly cooling to-10 to-5 ℃, stirring for crystallization for 2 hours, after the crystallization is finished, filtering, washing a filter cake by using a small amount of ethyl glacial acetate, placing the obtained wet product in a vacuum oven, controlling the temperature of the oven to be about 35 ℃ for drying treatment, and obtaining 37.5g of intermediate IV type compound lactonization product with the molar yield of 95.2%.
The following procedures for synthesizing hydrochloride salts of cefcapene lactone compounds are the same as those in example 6 and are not repeated herein.
Example 8
Dissolving 30.2g (0.096mol, 1.2eq) of (Z) -2- (2-tert-butoxycarbonylaminothiazole-4-yl) -2-pentenoic acid and 18.4g (0.08mol, 1eq) of hydroxymethyl-7-aminocephalosporanic acid in 300mL of ethyl acetate at normal temperature, slowly cooling to 5-10 ℃, controlling the temperature, beginning to dropwise add a mixed organic base of 8.1g (0.08mol, 1.0eq) of diisopropylamine and 2.4g (0.024mol, 0.3eq) of triethylamine, controlling the temperature to 5-10 ℃ after dropwise adding, and stirring for condensation reaction for 3 hours; after the condensation reaction is finished, triethylamine is dripped into the reaction liquid, the pH value of a system of the reaction liquid is adjusted to be 9.0-9.5, after the pH value is basically stable, the temperature is controlled to be about 15 ℃, stirring is carried out for full lactonization reaction for 2 hours, after the lactonization is finished, reduced pressure concentration is carried out until a certain volume is removed, then, the temperature is slowly reduced to-10 to-5 ℃, stirring is carried out for crystallization for 2 hours, after the crystallization is finished, filtration is carried out, a filter cake is washed by a small amount of ethyl glacial acetate, an obtained wet product is placed in a vacuum oven, drying treatment is carried out when the temperature of the oven is controlled to be about 35 ℃, and after drying, 37.4g of the intermediate IV compound lactonization is obtained, and the molar yield is 94..
The following procedures for synthesizing hydrochloride salts of cefcapene lactone compounds are the same as those in example 6 and are not repeated herein.
The solvent ethyl acetate in the condensation reaction liquid in the embodiment can be replaced by ethanol, and the corresponding product can be obtained as well.
Comparative example 1
In order to verify the importance of adding organic base directly after the condensation reaction in step A on the influence of pH control on the yield and purity of the lactone of the intermediate compound of formula IV, this comparative example is illustrated by adjusting the pH to 10-10.5 with inorganic base.
Dissolving 30.2g (0.096mol, 1.2eq) of (Z) -2- (2-tert-butoxycarbonylaminothiazole-4-yl) -2-pentenoic acid and 18.4g (0.08mol, 1eq) of hydroxymethyl-7-aminocephalosporanic acid in 300mL of ethyl acetate at normal temperature, slowly cooling to 5-10 ℃, controlling the temperature, beginning to dropwise add 10.5g (0.104mol,1.3eq) of triethylamine, controlling the temperature to 5-10 ℃ after dropwise adding, and stirring for condensation reaction for 3 hours; after the condensation reaction is finished, dropwise adding a sodium hydroxide solution with the mass concentration of 6% into the reaction solution, adjusting the pH value of the system of the reaction solution to 10-10.5, after the pH value is basically stable, controlling the temperature to be about 15 ℃, stirring for full lactonization reaction for 2 hours, after the lactonization is finished, carrying out reduced pressure concentration until a certain volume is removed to remove part of the solvent, then slowly cooling to-10 to-5 ℃, stirring for crystallization for 2 hours, after the crystallization is finished, filtering, washing a filter cake with a small amount of ethyl acetate, placing the obtained wet product into a vacuum oven, controlling the temperature of the oven to be about 35 ℃, carrying out drying treatment, and obtaining 13.8g of the intermediate compound lactonization product of the formula IV with the molar yield of 35%.
The specific embodiments described herein are merely illustrative of the spirit of the invention. Various modifications or additions may be made to the described embodiments or alternatives may be employed by those skilled in the art without departing from the spirit or ambit of the invention as defined in the appended claims.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
Claims (10)
1. A process for the preparation of a cefcapene lactone compound or a hydrochloride salt thereof, which comprises the steps of:
A. in the presence of a catalytic amount of organic base I, carrying out condensation reaction on a compound (Z) -2- (2-tert-butoxycarbonylaminothiazole-4-yl) -2-pentenoic acid shown in a formula II and hydroxymethyl-7-aminocephalosporanic acid shown in a formula III in an organic solvent, after the condensation reaction is finished, continuously adding organic base II to adjust the pH value of a system of reaction liquid to 9.0-9.5, and continuously stirring to fully lactonize an intermediate in the reaction liquid to obtain a lactonized intermediate compound shown in a formula IV:
B. under the action of Lewis acid, carrying out deprotection reaction on the intermediate compound shown in the formula IV in a water-insoluble organic solvent to remove BOC groups, and obtaining a corresponding product compound shown in the formula I:
when synthesizing cefcapene lactone compound hydrochloride, the following step C is also included after step B:
reacting the compound shown in the formula I with hydrochloric acid to obtain corresponding cefcapene lactone compound hydrochloride of the compound shown in the formula V:
2. the process for preparing cefcapene lactone compound or the hydrochloride thereof according to claim 1, wherein the organic base I and the organic base II in step A are independently one or more selected from triethylamine, diethylamine, pyridine, piperidine, diisopropylamine and pyrrole.
3. The process for preparing cefcapene lactone compound or the hydrochloride thereof according to claim 2, wherein the first organic base is a mixture of triethylamine and diisopropylamine, and the ratio of the diisopropylamine to the triethylamine is 1: 0.2 to 0.3.
4. The process for preparing cefcapene lactone compound or hydrochloride thereof according to claim 1, wherein the condensation reaction in step A is carried out at a temperature of 0-10 ℃.
5. The process for preparing cefcapene lactone compound or the hydrochloride thereof according to any one of claims 1 to 4, wherein the organic solvent in step A is one or more selected from ethanol, methanol, ethyl acetate and dichloromethane.
6. The process for preparing cefcapene lactone compound or the hydrochloride thereof according to any one of claims 1 to 4, wherein the Lewis acid used in step B is selected from titanium tetrachloride and/or aluminum trichloride.
7. The process for preparing cefcapene lactone compound or the hydrochloride thereof according to any one of claims 1 to 4, wherein the water-insoluble organic solvent in step B is one or more selected from dichloromethane, chloroform and ethyl acetate.
8. The process for preparing cefcapene lactone compound or the hydrochloride thereof according to any one of claims 1 to 4, which further comprises the following post-treatment after the deprotection reaction in step B:
controlling the temperature of the reaction solution after the deprotection reaction to be between 15 and 25 ℃, adding a proper amount of water, stirring, standing for layering to remove a water phase, and collecting an organic phase;
and adding a proper amount of water into the collected organic phase, adding an inorganic alkali reagent to react and adjust the pH value of the system to 6.5-8.0, standing and layering to remove the water phase after the reaction is finished, and collecting the organic phase.
9. The process for preparing cefcapene lactone compound or the hydrochloride thereof according to any one of claims 1 to 4, wherein the deprotection reaction in step B is carried out at a temperature of 15 ℃ to 25 ℃.
10. The process for preparing cefcapene lactone compound or the hydrochloride thereof according to any one of claims 1 to 4, wherein the molar ratio of the compound (Z) -2- (2-tert-butoxycarbonylaminothiazole-4-yl) -2-pentenoic acid of formula II to the compound of formula III, hydroxymethyl-7-aminocephalosporanic acid in step A is 1.0 to 1.5: 1.0, the molar ratio of the organic base I to the hydroxymethyl-7-aminocephalosporanic acid compound in the formula III is 1.0-1.5: 1.0; the molar ratio of the intermediate compound shown as the formula IV to the Lewis acid in the step B is 1.0: 1.5 to 3.0.
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| CN114540454A (en) * | 2022-03-09 | 2022-05-27 | 浙江东邦药业有限公司 | Method for synthesizing cefcapene pivoxil hydrochloride by enzyme method and synthetic intermediate thereof |
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| WO2008155615A2 (en) * | 2007-06-18 | 2008-12-24 | Orchid Chemicals & Pharmaceuticals Limited | An improved process for the preparation of cephalosporin antibiotic |
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| WO2008155615A2 (en) * | 2007-06-18 | 2008-12-24 | Orchid Chemicals & Pharmaceuticals Limited | An improved process for the preparation of cephalosporin antibiotic |
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| CN114540454A (en) * | 2022-03-09 | 2022-05-27 | 浙江东邦药业有限公司 | Method for synthesizing cefcapene pivoxil hydrochloride by enzyme method and synthetic intermediate thereof |
| CN114540454B (en) * | 2022-03-09 | 2023-10-17 | 浙江东邦药业有限公司 | Method for synthesizing cefcapene pivoxil hydrochloride by enzyme method and synthesis intermediate thereof |
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